Edward "Eddie" Morra (Bradley Cooper) is a writer who lives in New York City and has recently been dumped by his girlfriend Lindy (Abbie Cornish) in addition to failing to meet the deadline to turn in his new book, which he hasn't started yet. One day, Eddie comes across Vernon Gant (Johnny Whitworth), the brother of his ex-wife, Melissa Gant (Anna Friel). Vernon is a drug dealer, and he offers Eddie a sample of a new nootropic drug, NZT-48, claiming it has the ability for humans to access 100% of the brain's power, as opposed to the normal 20%. Eddie accepts, and, much to his surprise, the drug does indeed work, allowing him to finish his book.



Eddie asks for more of the drug, but he finds Vernon murdered and calls the police. He deduces that Vernon was probably killed by someone who wanted his stash. He finds the NZT and a wad of cash and uses them to turn his life around. He abandons his writing career and starts trading stocks, borrowing capital from a Russian mafia thug, Gennady (Andrew Howard).



Eddie becomes rich at an incredibly fast pace and is soon employed by the powerful businessman Carl Van Loon (Robert DeNiro). Eddie also gets back together with Lindy. He is followed by a man in a tan coat (Tomas Arana). He also starts using more and more NZT, causing side effects to occur: lost time, frenetic activity, and heart palpitations.



Eddie fails to accomplish a task assigned by Van Loon because of an NZT hangover, and fears he might even have killed a woman (Caroline Winberg). Suffering severe withdrawal symptoms due to the post-hangover attempt to quit NZT cold turkey, Eddie begins to feel incredibly sick and he turns to Lindy for help, revealing his addiction to NZT. Reluctantly Lindy agrees to retrieve his stash, hidden in her apartment and return it to him at her office.



However, on the way back to Eddie, Lindy is intercepted en route by the man in the tan coat, and it becomes obvious that he is dangerous, as he gives chase to Lindy, killing two would-be saviors as she flees. Eddie by phone convinces her to take one of the pills, and Lindy makes a bold escape. Though Eddie is saved, Lindy is convinced that he will destroy himself because of NZT and breaks up with him again. He is contacted by ex-wife Melissa and learns that she had been an NZT addict. Worse, he learns that withdrawal from the drug causes major health and mental problems, possibly resulting in death. She warns Eddie to taper off the NZT before it is too late.



Gennady tries one of Eddie's pills, realizes the effects and threatens Eddie until he agrees to give him more NZT. Despite Melissa's warnings, Eddie manages his consumption of the drug down to an acceptable level, then uses his fortune to hire a scientist to work on reverse engineering NZT, a process that could take years.



He assists Carl on a corporate merger deal with rival businessman Hank Atwood (Richard Bekins). Before the deal can take place, Atwood falls ill. Noticing the man in the tan coat working with Atwood, Eddie realizes the man's true mission — to steal Eddie's stash of NZT for his boss, whose real illness is NZT withdrawal. The stash is stolen by Eddie's lawyer, Brandt (Ned Eisenberg), who is revealed to also be working for Atwood.



Eddie is followed home, but manages to kill Gennady and two thugs with intelligence gained from what he believes to be the last of the NZT, which he drank directly from the deceased Gennady's bloodstream. Atwood dies, Brandt having kept the NZT for himself. Eddie agrees to work with the man in the tan coat to retrieve his stolen NZT at Brandt's house.



One year later, Eddie's book has been published (titled Illuminating the Dark Fields — a reference to the novel on which the film is based), and Eddie is running for the United States Senate. In the midst of his campaign, Carl approaches Eddie with the revelation that he bought the company producing NZT and that the backroom NZT lab Eddie was financing has been shut down.



Carl offers him an unlimited supply of NZT (admitting that they both know he is headed for Presidency); however, Eddie must use his political position to push Carl's agenda in return. Eddie refuses, claiming that he no longer needs the drug: his prolonged use, he says, has allowed him to come off of the drug and has permanently enhanced his brain. The viewer is left to decide whether he's telling the truth or not.



(In the alternate ending available on DVD, Eddie still rejects Van Loon's proposal. But it is then revealed Eddie is not off NZT, and vows that he will find a way out, saying, "Isn't that what the pill does?")