The family of Harlan Thrombey, a wealthy mystery novelist, attends his 85th birthday party at his Massachusetts mansion. The next morning, Harlan's housekeeper, Fran, discovers him dead with a slit throat. Police detectives Lieutenant Elliot and Trooper Wagner believe Harlan committed suicide, but private detective Benoit Blanc is anonymously hired to investigate. Blanc learns that Harlan had strained relationships with his family members, giving several of them possible motives for murder.
Unknown to Blanc, Harlan's nurse, Marta Cabrera, believes she injected Harlan with a lethal dose of morphine after mixing up his medications the night after the party. Harlan instructed her to create a false alibi and then slit his own throat. Marta cannot lie without vomiting, so she gives accurate but incomplete answers when questioned. She agrees to assist Blanc's investigation and conceals evidence incriminating her. At the reading of Harlan's will, Marta is bequeathed his entire fortune, stunning the Thrombeys. Harlan's grandson Ransom helps Marta escape the family, but coerces her into confessing to him. He offers help in exchange for a portion of Marta's inheritance. Meanwhile, the remaining Thrombeys try to persuade or threaten Marta into renouncing the inheritance, to no avail.
Marta receives a blackmail note containing a partial photocopy of Harlan's toxicology report. She and Ransom drive to the medical examiner's office to find it burned down. Marta receives an email proposing a rendezvous with the blackmailer. Blanc and the police spot them, and after a brief car chase, Ransom is arrested. At the rendezvous, Marta finds Fran drugged. She performs CPR and calls an ambulance. She confesses to Blanc but discovers that she's already been implicated by Ransom. Out of moral obligation, Marta believes she must confess to the Thrombeys, which would invalidate the bequest under the slayer rule.
Back at the mansion, Marta finds Fran's copy of the full toxicology report, which shows Harlan had only trace amounts of morphine in his blood. Blanc reveals his deductions to the police, Marta, and Ransom: that Harlan had told Ransom about his will, and that Ransom had then swapped Harlan's medicines to ensure that Marta would accidentally kill him and thus be ineligible to claim the inheritance. However, Marta actually gave Harlan the correct medication, recognizing it without reading the label due to her experience as a nurse, she was able to differentiate between the medications based on their viscosity; she only thought she had poisoned him after reading the label. When the death was reported as a suicide, Ransom anonymously hired Blanc to expose Marta. Fran saw Ransom tampering with the crime scene and sent him the blackmail note. After Ransom realized Marta was not responsible for Harlan's death, but Marta still thought she was, he forwarded the blackmail letter to Marta and burned down the medical examiner's office to destroy evidence of her innocence. He then overdosed Fran with morphine, intending for Marta to get caught with Fran's corpse.
The hospital calls; Marta relays that Fran survived and will implicate Ransom. He scoffs that since his attempt to kill Fran failed, his lawyers will help him escape arson and attempted murder charges. Marta then vomits on him, revealing that she lied: Fran is dead. Realizing he has confessed to the murder, with the conversation being recorded, Ransom attacks Marta with a knife from Harlan's collection, which turns out to be a retractable stage knife. The police promptly arrest him.
Blanc tells Marta he suspected early on that she played a part in Harlan's death, noting a drop of blood on her shoe. He tells her that her innocence prevailed because she made ethical choices all along that frustrated Ransom's attempts to incriminate her. As Ransom is taken into custody, Marta watches from the balcony of what is now her mansion, with the Thrombeys gathered outside.
