Lupin decides to steal digital currency from Marco Polo on the dark web and enlists the aid of the developer of the security system of the bank: Ami. She lives in one of the Twin Towers, the one below water, but is weak from living on a poor diet. With Ami's help, they successfully transfer a fortune into Lupin's account. However, almost immediately upon their return to their hideout, Zenigata and his men surround the place. They discover that Zenigata easily found them because a new online game, "Arrest Lupin III" has gone viral with people posting sightings of Lupin. A chase ensues, with Lupin becoming increasingly frustrated at the intense pursuit.

The chase continues, with Lupin, Daisuke, Goemon and Ami arriving at an airport. They steal an electric car, but become trapped in a hangar by Zenigata and surrounded by the police. Within the hangar is an AW609 airplane, and with Ami's hacking skills, and the energy from the electric car battery, they start the plane and escape. They then board a cruise ship to Bwanda which is not an ICPO member nation so Zenigata cannot touch them. While there Ami wanders off and is attacked by street thugs, but is rescued by Lupin. They discuss her relationship with the team and Lupin says that she should stay with them for protection from Marco Polo. Suddenly they come under attack from bounty hunters. There is now a new online game, betting on the day Lupin will die.

Shinpei Mayama, the Rat Clan, Union Mama... the all-stars of assassination, from all over the world, suddenly come after Lupin. They're players in a new game started by the executives of Marco Polo: Happy Deathday. Ami uses her hacking to get Lupin out of trouble, but she's shot and injured in the process. With Jigen and Goemon also under assault, Lupin comes up with a plan to take out all the hired killers at once.

Fujiko smiles deviously as she points her gun at Lupin, when Zenigata arrives to save him and Ami. They get into the inspector's car which takes off, but it's soon attacked by soldiers who are trying to cash in the price on Lupin's head. Abandoning the car, they have to cross the desert on foot, a difficult task made harder by the presence of Zenigata!

After Lupin's publicized demise, Ami is taken in by Zenigata, who has been demoted to narcotics for aiding and then losing Lupin. Soon after receiving a letter from Goemon, Ami contacts Marco Polo and proceeds to their headquarters in order to work out a deal. Marco Polo's CEO, Chuck Glay, instead catches her in a deathtrap, threatening to kill her unless she spills everything about Lupin, including the whereabouts of the money he purloined from Marco Polo. However, this scenario is revealed as a trap set by Lupin for Glay and his fellow instigators of the Happy Deathday game, using Ami's hacking expertise and the aid of his associates Jigen, Goemon and Fujiko. Zenigata, who knew Lupin was too clever to be killed so easily, collars Glay for drug dealing, and Ami, inspired by her experiences, enrolls at a girls boarding school to catch up on the real life she has missed.

In order to save their family workshop from foreclosure, the younger brother suggests to his brainless older brother that Lupin may be the answer to their financial problem. They build a smart safe for the Greater Tokyo Bank which can only opened by someone with no brainpower, as a special challenge to Lupin, the world's greatest thief. Stung by the resilience of this obstacle, Jigen, Fujiko and Goemon begin to implement a sadistic sleep deprivation, beating and exercise regime to kill off Lupin's brain cells. However, at the publicized event of the safe's opening, Lupin instead consumes lots of blueback fish, boosting his brains so that the safe's IQ counter is overloaded and resets itself, thus opening the safe. While the contest ends in a draw, the brothers become celebrities and begin selling canned fish, recovering their property.

Lupin is hired by his old friend Gaston to steal a certain painting - a Picasso forgery ostensibly painted by Gaston's grandchild - from the vault of Mr. B, a compulsive art collector. Lupin succeeds in his heist, but discovers in short order that the Gaston who hired Lupin was an impostor, since the real one died a month ago, and that the painting is the hiding-place for a notebook containing information about high-level crimes hushed up by the French police, evidence which would topple a number of high-level personnages if its contents went public. For this, he and Jigen end up chased by the DSGE and Albert, an old - and unfavored - individual from Lupin's past.

At Gaston's grave, Lupin and Jigen encounter Camille Bardot, an ex-investigator with a phenomenal photographic memory and an old acquaintance of Gaston. After receiving a telephonic challenge from Albert, the three of them find themselves targeted by a number of assassins. Mortally wounded, Bardot reveals that he aided Gaston in copying the original black notebook in the hopes that, at the right time, justice could be served against the perpetrators, but in turn they were ruthlessly hunted by DGES director Guillaume for it. Realizing that Albert set him up to gain possession of the notebook, Lupin returns to Paris to challenge him; but despite his precautions, Albert gets the drop on him, shoots him severely, and recovers the notebook.

Before Albert's triumph is complete, Lupin is rescued by Jigen and Goemon, and the notebook is snatched from him by assassin-for-hire José and his minions. While recovering, Lupin reveals that Albert used to be his partner years ago but, not being satisfied with "small-time" thefts, turned away from Lupin to become the shadow ruler of France. Meanwhile, with the presidential elections approaching, José uses the book as leverage against the government, allowing terrorists to wreak havoc with impunity in order to swing public favor toward his patron, the right-winged election candidate Calvess. He also has his gang pursue Lupin and his friends because of their knowledge of the book's contents. With their respective interests at stake, Lupin and Albert join forces against their common enemy.

After forcing the DGES Director General to reveal everything he knows about José, Lupin and Albert, assisted by Jigen and Goemon, storm the chief assassin's chateau and fight their way past Jóse's chief henchmen. When they find him and bring him down, Jóse, a cyborg, kills himself with an implanted bomb, but Lupin manages to retrieve the notebook. Despite Albert's final attempt to steal it back, Lupin retains his hold on it, and the two part ways with their past relationship (somewhat) restored. After Calvess and the DGES Director General are left defeated, Lupin re-buries the notebook in Gaston's grave.

Just before New Year's Day, Lupin remembers a former caper in which he and his gang attempted to grab the legendary collection of Pablo, a notorious drug kingpin who disappeared in the South American jungle. Eventually they discovered Pablo's secret hideaway for his collection of first-class vintage cars, but found themselves challenged by a car which was strangely invulnerable to their attacks. Lupin dared his opponent to a race across Pablo's old jungle race track and won; the challenger was revealed to be the ghost of Pablo himself, and his car collection, long since overcome by degradation, to be nothing but scrap metal. In addition, they were hunted by Pablo's surviving family members, who were after the collection themselves, and their corrupt Brazilian Army cohorts. Although initially intent on fleeing on their own, Lupin, Jigen and Goemon ended up battling their pursuers together, while Fujiko just barely made her escape alone.

Goemon is coerced by Lupin into to winning the confidence of the young woman Chloé Cazal. She was apparently a close friend of the late Belgian millionaire André Regnie, who gave her an immensely valuable gem necklace made before the Russian Revolution, which has made Chloé a target for the descendants of its original owners. While looking for her in the town of Sirena (and struggling with the attention of a local Anicon's visitors), Goemon befriends a boy named Jean who lives in Chloé's neighbourhood. He moves into Jean’s parents' hotel to watch over her, spending all his money on expenses and fending off several hired assassins in the process. However, Goemon later discovers that the girl is actually the Chloé's daughter Inés, and that her necklace is a forgery. Inés had acted as bait to enable her mother to sell the real necklace. In the end, with no money left, Goemon asks to stay with Inés to work off his accumulated hotel bill.

Lupin's next target is the Bloody Teardrop, a national treasure of the south-east Asian kingdom of Padar which is currently worn by the royal princess Dolma, a very independent and forceful girl. As fate wills it, Dolma attends the same boarding school as Ami and has even - as a fellow oddball - become friends with her. A terrorist group calling itself the Whales of Liberation occupy the school and takes the students and teachers (including Fujiko, who has infiltrated the institute for the jewel) hostage. Fujiko frees Ami, and they team up to take them down from within, aided by Lupin's gang, who have also discovered the terrorists' presence. However, one of the teachers reveals himself as McGuire, a CIA special agent, who prepares to spirit Dolma away because, as he states, Pandar is in danger.

Padar is (in more ways than just within its population) divided between reformist and traditionalist elements who respectively promote and oppose the country's advancement into the high-tech age. Lupin and company travel to Padar to track down Princess Dolma and nab the Bloody Teardrop, as does Fujiko with a grudging Ami in tow. As they all investigate the princess' whereabouts, they stumble right into an imminent coup d'état committed by Padar's High Priest, the leader of the traditionalists, and covertly supported by Padar's army and the American government, which plans to depose the old king and install Dolma as a puppet ruler. Lupin and Ami sneak into the royal palace to unite with Dolma, but then suddenly Lupin finds himself shot by one of the princess' arrows.

Betrayed by Dolma, Lupin and Ami escape with the aid of Fujiko, who has also claimed the Bloody Teardrop. The king has gone into hiding, whereupon the revolutionists declare martial law in the city in order to capture him and force him to abdicate. It also turns out that McGuire is really Ugo, a native Padarian, who was originally tasked with assassinating the princess, but has switched sides in order to prevent his country from sliding into open civil war. Dolma has decided to join the traditionalists in order to eventually defeat them from within, knowing that she will otherwise not stand a chance without the support of her subjects. Fujiko and Ami evade the army with Lupin in their care, but Fujiko soon abandons the two to fend for themselves. Just before they can be captured, the king, assisted by the communications conglomerate Shake Hands, successfully stages a counter-revolution; and at that critical moment, Lupin finds himself confronted by Fujiko about his true feelings for her.

Lupin and Ami sneak back into the capital city in disguise to steal Dolma away from her coronation, and Jigen and Goemon, worried about Lupin's absence, also head for the royal palace. As the revolt begins to collapse, the High Priest resorts to fleeing and establishing an independent regime with or without Princess Dolma and the Bloody Teardrop, thereby showing his true colors. This last coup is foiled by Lupin and his crew, and Ami secretly broadcasts the Priest's desperate attempt to cut a deal with Lupin across the internet and public channels, losing him all of his remaining allies. Dolma takes charge of Padar, publicly solidifying its sovereignty and reuniting her people, and in the aftermath Ami tells Lupin about her feelings for him.

Countess Isabelle de Maunbassant, an old acquaintance of Lupin, has invited him to catch the murderer of her husband Philippe, offering him her husband's emerald ring as a reward. She invited the three suspects to her chateau in order to set a trap for the culprit: gem collector Frederick Autorett, the count's nephew Allan Dubois and failed businessman Pierre Schmidt. However, in the midst of her announcement, a blackout hits the chateau and the Countess is fatally shot. Just before she dies, she seals off the chateau, giving Lupin time until dawn to find the murderer. Posing as Jim Barnett, a private eye, and assisted by Isabelle's maid Marie, Lupin quickly finds and exposes the culprits: Allan Dubois and his twin brother, who secretly entered the chateau and committed the murder. With the case solved, Lupin respectfully leaves the ring with the Countess and invites Marie to join him in a prospective career change as a private investigator.

One day, Lupin finds his hotel room's toilet clogged. The resulting sanitary restriction, their need for secrecy, and Goemon's strict preference for Japanese cuisine creates friction among Lupin's gang. This is not helped when Fujiko unexpected appears, apparently let in by a drunk Lupin the previous night. While they wait for the plumber, Fujiko begins to act secretively about the bathroom, and they suspect one of her usual schemes against them. The situation becomes more complicated when a passing Zenigata is attracted by the smell of Goemon's cooking and pays a brief visit. In the end, it transpires that Fujiko had dropped by for a special anniversary between herself and Lupin, complete with a gift which she hid in the toilet's water tank, inadvertently causing the blockage.

Lupin is "invited" by a psychotic millionaire named Zylberstein, one of his old acquaintances, to a solitary chess game for life and death. To increase the thrill, Zylberstein has hired an infamous female sniper named Mirage, a former partner of Jigen, to kill Lupin during the game. This results in a deadly hide-and-snipe match between Jigen and Mirage amidst a ruined mountain city, which ends when Jigen manages to critically damage Mirage's rifle just as she is taking aim at Lupin. The resulting ricochet hits Zylberstein instead. Lupin and Jigen discover the sniper is Mirage’s daughter, who took the job to finance her sick mother's transfer to a better hospital. Lupin leaves the monetary stake Zylberstein left him (in case Lupin won the game) to Mirage’s daughter, and Jigen dissuades her from pursuing a mercenary's life.

Lupin, Jigen and Goemon take a trip to one of their old haunts in Russia to carry out some easy heists. To their surprise, they find another party of thieves already raiding the same targets with their old enemy Zenigata among their ranks. When Lupin talks with Zenigata, he finds that the latter has alcoholic amnesia from a massive drinking bout after another failure to catch Lupin. Zenigata has adopted the alias "Monety" and the modus operandi of his old nemesis Lupin while trying to uncover his lost identity. Unwilling to leave Zenigata in that condition, Lupin and company intercept Zenigata at the site of his next heist. When Lupin and Zenigata escape the crime scene together, the encounter finally snaps Zenigata's memory back into place, and to everyone's relief their relationship returns to its usual state.

Enzo Bron, the president of the global IT company Shake Handz, officially presents his company's new app called PeopleLog, a service linking facial recognition with global databases to create publicly accessible personal profiles. Lupin and company soon find that PeopleLog has become widely used to check people's identities, making it impossible for them to appear in public and easy for the police and Lupin's enemies to track his movements. Also, the apparent reliability of PeopleLog easily sways public opinion, and the world's governments become concerned that the app may cause political control to slip from their hands. As Lupin and Jigen head to rejoin Goemon, who has retreated into the mountains, they encounter Zenigata, who tells them that Fujiko has been captured by Enzo.

PeopleLog has stirred doubts within Goemon about whether Lupin sees him as an equal partner, but he still rejoins Lupin, Jigen and Ami to infiltrate the headquarters of Shake Handz on Olig Island in the Republic of Maul. Ami initiates a massive DDoS on the Shake Handz network system to mask their movements, but Enzo has anticipated this event and executes a counterattack. Goemon, left behind to cover the team's retreat, is challenged by Enzo, who fans Goemon's lingering doubts about his relationship with Lupin. Just as Lupin and Ami are about to liberate Fujiko, Goemon intervenes, demanding a duel to clarify things between them and draws his sword, Zantetsuken. Lupin ends up critically wounded and Ami pleads with Enzo - whom she knows to be her father - to save Lupin's life.