The movie opens in May 2020, amid the early chaos of the COVID-19 pandemic, setting a tense and uncertain backdrop. Connecticut Governor Claire Debella is seen conducting a remote interview when she unexpectedly receives a mysterious package. Simultaneously, scientist Lionel Toussaint is participating in a video call with his superiors at Alpha Industries, who are urging him to reconsider the dangerous implications of his boss, Miles Bron, and his latest risky project. Soon, Lionel receives the same enigmatic package from Miles.
Elsewhere, at a lively party, supermodel Birdie Jay is being looked after by her overwhelmed assistant Peg. They too receive the package from Miles, and Peg tries to keep Birdie from getting too drunk or distracted by her phone. Meanwhile, Duke Cody, a popular Twitch streamer, is filming with his girlfriend Whiskey when his mother informs him about the package.
All four — Claire, Lionel, Birdie, and Duke — quickly realize they are connected through these mysterious boxes and hop on a group call to figure out what to do. The first step involves deciphering the package, which leads to a series of puzzles. These puzzles eventually point to a model of a building and an invitation from Miles to his private island for the weekend. The last recipient, Cassandra “Andi” Brand, decisively smashes her box to pieces before discovering the invitation inside.
Meanwhile, detective Benoit Blanc is shown in a bathtub on a video call with renowned figures including Natasha Lyonne, Angela Lansbury, Stephen Sondheim, and Kareem Abdul-Jabbar, expressing concern over his self-isolation. His partner, Philip, then informs him that he’s also received a mysterious package. Blanc later joins the arriving guests at a dock, where they board a ship bound for Miles’s secluded island. Each guest, excited and curious, discusses their relationships with Miles and their anticipation of the upcoming murder mystery game he’s arranged, where Miles claims to be the victim.
However, it becomes clear that Miles didn't actually invite Blanc—who, despite this, receives an invitation on his own. As they arrive, Miles welcomes his guests along with a mysterious guest named Derol. He introduces his luxurious home, the Glass Onion, naming it after a favorite bar they all used to frequent, and announces that they will participate in a murder mystery game where he is the "victim." Blanc meets Andi for the first time, sensing the tension from their past, especially since her relationship with Miles ended badly.
The guests settle in, with activities including a dip in the pool and drinks with a secret kick. Throughout the evening, Miles gives a speech, but tempers flare when Andi confronts him over his manipulative ways and the greed that drove their past conflicts. Peg presses Miles about a sweatshop connected to Birdie's clothing line, but Miles dismisses her concerns. Blanc, attempting to relax, tries to enjoy a cigar but is thwarted by an alarm, and notices Duke catching Miles and Whiskey in an intimate moment.
As the night progresses, Miles holds a gathering with drinks, where they begin the planned murder mystery. Blanc quickly deduces that Birdie is the intended culprit, as a hidden device might have used a crossbow to "kill" Miles—though the simulated attack leaves everyone impressed and perplexed. Miles then reveals his secret project: a new fuel called Klear, which powers the Glass Onion. Lionel warns him that the fuel still needs elaborate testing, raising questions about its safety and the potential for future disasters.
Tensions increase when Duke shows Miles an article that could make him a star journalist, suggesting ambitious plans for Duke’s career. Miles offers him a drink, but soon after, Duke chokes and dies from an allergic reaction—prompting suspicion that Miles poisoned him. The group's panic grows when Duke’s phone is missing, and the power suddenly cuts out, plunging the party into darkness.
Amidst chaos, Whiskey rushes in yelling that Andi—who was considered to have a troubled past—has been attacked. In the darkness, an unseen attacker shoots Andi, collapsing her to the floor. Blanc finds her wounded, and everyone assembles in a different room, trying to make sense of the situation.
The story then flashes back to Blanc receiving the invitation and being approached by Helen, Andi’s twin sister, who delivers a smashed puzzle box. She claims Andi was murdered, not suicidal—suggesting Miles played a role by secretly stealing her ideas and isolating her from their circle. Helen believes Miles is the real villain and that Andi’s death was orchestrated to cover his trail.
Blanc proposes that Helen disguise herself as Andi and attend the island gathering to gather critical evidence. Though hesitant, Helen agrees, adapting her appearance and voice to blend in. On the island, Helen uncovers disturbing truths: Lionel and Claire are worried about the dangerous impact of Klear; Birdie confesses to signing a statement taking responsibility for sweatshop issues so Miles can leverage her fame; Whiskey reveals her dissatisfaction with Duke, who manipulated her into pretending to seduce Miles for a career boost.
Helen sneaks through the estate, covertly recording conversations and searching for incriminating evidence. When Duke is murdered, Whiskey catches Helen in her room at gunpoint, leading to a tense standoff. The blackout gives Helen a chance to escape, and Blanc assists her in faking her death using some hot sauce and a fake corpse, allowing her to continue her investigation unnoticed.
Eventually, Helen finds the envelope containing proof of Andi's true plans—hidden in Miles’s office—but Miles quickly burns it to destroy the evidence. Blanc publicly exposes Miles’s deception, revealing that Miles orchestrated Duke’s death to silence him over blackmail material—a plan that involved planting the poisoned drink. It’s also uncovered that Miles had killed Andi after discovering she intended to expose his theft of her ideas. Her body was concealed to look like a suicide, but Helen’s evidence and her confrontation reveal the truth.
As chaos erupts, Helen ignites a final act of revenge by tossing a sample of Klear into the fire, causing a massive explosion that destroys the Glass Onion and Miles’s estate. Helen also sacrifices the Mona Lisa, burning it to eliminate any remaining proof of Miles's treachery. With Miles’s empire reduced to ashes, the remaining guests, including Blanc, decide to testify against him as police arrive to arrest him.
The film concludes with Helen, fulfilled by her justice, looking out over the ocean with a smirk of satisfaction, knowing she’s finally avenged her sister and exposed the truth behind the deadly scheme.
