In 1976, eight years following the events of the original movie, 11-year-old Gru (Steve Carell) becomes the new leader of the Minions. Everything takes a turn when Gru receives an invitation to audition for the Vicious 6, a notorious criminal organization founded by the super-villain Wild Knuckles (Alan Arkin). After Knuckles' demise, the group is now led by the ambitious Belle Bottom (Taraji P. Henson), who is on the lookout for a fresh recruit. The Vicious 6 also includes characters like Jean-Clawed (Jean-Claude Van Damme), who sports a massive mechanical lobster claw in place of his right arm, and Nunchuck (Lucy Lawless), a nun skilled in wielding nun chucks. They are joined by Svengeance (Dolph Lundgren), a roller-skating enthusiast, and Stronghold (Danny Trejo), who possesses enormous metal hands.
The plot thickens when Wild Knuckles embarks on a mission to steal a stone imbued with magical powers. After successfully snatching the stone, he evades an army of evil minions guarding it. However, during his rescue by Belle Bottom, he faces betrayal and the entire gang abandons him, leaving him for dead. Belle, scheming to harness the stone's power, plots to annihilate the Anti-Villain League.
Meanwhile, Dr. Nefario (Russell Brand), an absent-minded scientist operating a record store called Criminal Records—unknown to him, a front for the Vicious 6—continues his daily routine. Gru, aspiring to be a supervillain, applies for a position in the Vicious 6 and is invited for an interview. Although the interview doesn't go as planned, Gru manages to snatch a stone that can transform anyone into an animal from the Chinese Zodiac by the next Chinese New Year.
In a twist of fate, during an escape with Kevin, Stuart, and Bob (all voiced by Pierre Coffin), Gru discovers that Otto, a large, chatty Minion with braces, has bartered the stone for a pet rock he adored at first sight. Enraged, Gru dismisses the Minions and ventures out alone to reclaim the stone. Despite being thought dead, Knuckles is alive and has been trailing the Vicious 6, having witnessed Gru's theft of the stone. He abducts Gru and transports him to San Francisco.
Knuckles demands that the Minions deliver the stone in exchange for Gru. In a bit of sleuthing, they force Otto to divulge where he exchanged the stone, only to discover it has been given to a biker uncle. Setting off for San Francisco, the Minions, in an ambitious turn of events, commandeer a plane to rescue Gru. At Knuckles' hideout, they encounter challenges from his henchmen until they receive aid from Master Chow (Michelle Yeoh), a former Kung Fu teacher, who defeats the goons. After intense training, the Minions feel emboldened and return to confront Wild Knuckles.
As Otto pursues a biker (played by The RZA) who has the stone, he eventually manages to retrieve it and reunites with Gru in San Francisco. Gru and Knuckles begin to forge a bond after Knuckles’ loyal henchmen abandon him following a disastrous encounter with Chow. In a bold heist, they successfully steal the Mona Lisa from the Bank of Evil. However, chaos ensues when the Vicious 6 attack Knuckles’ residence, seeking revenge for Gru’s earlier actions.
During a climactic showdown at the Chinese New Year parade in Chinatown, Otto reunites with Gru, but they find themselves cornered by the Vicious 6, who are then confronted by the Anti-Villain League. Amidst the midnight chime, the Vicious 6 utilize the stone, transforming themselves into animals from the Zodiac, and kidnap Gru with malevolent intent. The Minions are transformed into a rabbit, a goat, and a rooster respectively.
Bravely returning, Knuckles engages Belle Bottom while the Minions harness their inner strength, inspired by Chow's teachings, to fend off the Vicious 6. Otto manages a daring rescue of Gru, who employs the stone's powers to turn the antagonistic crew into rats, leading to their eventual arrest. As Gru delivers a heartfelt eulogy at Knuckles' funeral, it’s revealed that Knuckles is alive, having faked his death. The story culminates with Gru and Knuckles driving off into the sunset together, joined once more by the Minions, who have been re-hired after their heroic actions.
As a delightful mid-credits twist, Gru offers a job to Dr. Nefario in gratitude for his ingenious invention that played a crucial role in the theft of the stone. Although Nefario initially declines the offer, he ultimately agrees to join Gru, and they set off in a jet, reminiscent of Gru's future escapades.
