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Business tycoon and billionaire Damian Hale (Ben Kingsley) is master of his own universe, until he is diagnosed with terminal cancer. Now on his deathbed, he finds a business card directing him to a man named Professor Albright (Matthew Goode), who informs him about a radical medical procedure called "shedding", in which one's consciousness is transferred to an artificially grown healthy body. Damian decides to undergo the procedure and engineers his own public death. Albright transfers him into a new body (Ryan Reynolds) and prescribes medication to alleviate vivid hallucinations which he claims are side effects of the procedure.
Damian starts a new life in New Orleans under the assumed name of Edward Hale and quickly befriends his neighbor Anton (Derek Luke). However, when he forgets to take his medicine, he subsequently suffers hallucinations of a woman and child. When Edward asks Albright about the hallucinations, he dismisses his concerns, but accidentally reveals that he knows details of the hallucinations that Edward did not reveal. Albright arranges for him to move to Hawaii for a change of scenery, but Edward, convinced the hallucinations are some kind of memory, researches a landmark he saw in his vision and heads to St. Louis instead.
In St. Louis, he encounters the woman, Madeline (Natalie Martinez), who identifies him as her apparently deceased husband Mark. Edward learns, much to his horror, that the body he is inhabiting belonged to another man who sold himself to Albright in order to gain the money he needed to cure their sick daughter. The two are attacked by Albright's men led by Anton, who reveals that he is one of Albright's employees. Mark and Madeline severely wound Anton, escape, and collect Madeline's daughter Anna from school before heading back to New Orleans. There, Mark researches Dr. Jensen (Thomas Francis Murphy), the man who invented shedding; Mark notices a tic he shares with Albright in a video of him and sees Albright in the same video as his assistant, and concludes that Jensen has shedded himself into Albright's body.
Mark finds Dr. Jensen's wife Phyllis in a nursing home suffering from Alzheimer's and tries to get her to reveal where his research is, but she does not know. Mark soon lures Albright to the home and confronts him. Albright gives him more medicine and reveals that the pills suppress the original personality of the body he is inhabiting; if he continues to take the medicine, his "Mark" personality will eventually be completely erased, while if he quits, the "original" Mark will reassert control over his body and kill Damian's personality instead. But Mark flees when more assassins show up, including another man who he recognizes as Anton due to a necklace they share; Anton reveals that he has sledded multiple times.
At a rest stop, Madeline confronts Mark over his behavior and lack of knowledge of their personal details, and he reveals all that has transpired to her. He takes them to his old friend Martin (Victor Garber) and convinces him to provide for Madeline and Anna to flee to the Caribbean. However, he and Madeline discover Anna playing with Martin's young son Tony (Dylan Lowe), who died two years ago; Martin admits that he used shedding to save his son and that Albright's men are waiting for them. Mark then reveals the dark secret behind shedding and flees to distract Albright's men while Martin, Madeline, and Anna escape. Mark manages to crash Anton's car with him in it and defeat his pursuers, but Madeline and Anna are recaptured.
Mark stops taking his medicine in order to experience more memories, hoping they will lead him to Albright. This succeeds, and Mark pursues Albright to a lab built in an abandoned warehouse. There, Albright captures him and attempts to shed Anton into Damian's original body, but Mark, remembering that metal interferes with the shedding process, takes a bullet casing in his mouth, therefore sabotages the procedure which kills Anton in the process. He rescues Madeline and Anna and takes down Albright once and for all. Mark arranges for Madeline and Anna to flee the country as planned, meets his own estranged daughter Claire (Michelle Dockery), and delivers her a letter reconciling with her. He then heads to the Caribbean and stops taking his medicine, dying peacefully. The real Mark reawakens in his own body and discovers a video message from Damian's personality thanking him for the time he gave him. Mark then reunites with his family at last.