Andrew Largeman (Braff) wakes up from a dream, in which he apathetically sits on a crashing plane, to a telephone message from his father (Holm), telling Andrew that he needs to return home because his mother has just died.

Andrew leaves Los Angeles and returns home to New Jersey to attend the funeral. He recognizes the gravediggers as old friends Mark (Sarsgaard) and Dave (Alex Burns), who invite him to a party that night at the house of an old friend of theirs, Jesse (Armando Riesco). After smoking marijuana, he takes ecstasy at the party but remains detached. He is impressed by the abundant usage of drugs; indeed, this is the last time he's seen taking any. At home, Andrew has his father book a doctor's appointment for headaches he's been having.

The morning after the party, Andrew proceeds to the appointment. In the waiting room, he meets a girl named Sam (Portman), who is a pathological liar. She later explains that most times she doesn't know why she lies and will always admit them afterward. In Andrew's meeting with his doctor (Ron Leibman), it's revealed that Andrew has been on lithium and other mood stabilizers, as well as antidepressants, for his entire adult life, but has stopped taking them. He also says that his father, who is also his psychiatrist, put him on the medications in the first place. Andrew finds Sam outside of the office, eventually offering her a ride home. Sam invites him into her house, and he meets her mother, who inadvertently reveals that Sam is an epileptic. During the visit, Andrew and Sam share a moment in which she explains her habit of occasionally making random motions and sounds, to fulfill her desire of doing something "completely original" that "no one else has ever done before". They then go outside to bury Sam's recently deceased pet hamster Jelly, upon which Andrew tells Sam of his mother's death and Sam tearfully eulogizes her hamster. After returning home, Andrew's father confronts him and is insistent that they have a talk before Andrew leaves town.

In the next scene, Andrew and Jesse sit in the cemetery as Mark digs another grave. Jesse idly describes how their town is "messed up" because of prevalent drug use and compares it to Brave New World, which he claims is by "Aldous Huxtable". Meanwhile, Andrew watches in shock as Mark uncaringly steals jewelry from the corpse he's burying.

Andrew then returns to Sam's house, and the two spend the rest of the day together, joining his friends later. Andrew tells her that when he was nine years old he pushed his mother in frustration, knocking her over a broken dishwasher in an accident that left her paraplegic; he says that his father blames him for his wife's paralysis and put him on his medications to "protect him" from the anger he supposedly harbors. Sam listens non-judgmentally, and Andrew subsequently admits his feelings for her.

The next day, Mark tells Andrew that he needs help "tracking down" a going-away present for him. Sam, Andrew, and Mark spend the day tracking the present down, ending in a quarry in Newark where Mark talks to junkyard owner named Albert (Denis O'Hare), who is employed with his wife Faye to prevent the construction of a shopping mall in the area, which is disputed due to the discovery of a rare subterranean chasm (referred to as the "infinite abyss") beneath the quarry. The three visitors discuss the reasons for which Albert and Faye chose to live there. Albert explains that living there and exploring the abyss is "doing something that's completely unique, that's never been done before", mirroring the earlier speech by Sam. Finally, Albert explains that what actually matters is his family, the camera right afterwards showing the listening Sam and Andrew. Andrew is inspired by the conversation, and outside in the rain, he climbs atop a derelict crane and screams therapeutically into the abyss, soon joined by Sam and Mark. He and Sam then share their first kiss.

When Mark and Andrew look at the gift later on, it turns out to be Andrew's mother's favorite pendant, one of the items Mark had stolen from a grave and sold, and subsequently relocated. Andrew eventually approaches his father for the talk the father had suggested, in which he says he was not to blame for his mother's accident and that, from now on, he will live his life without medication. He nevertheless forgives his father and says he wants to build a better relationship with him.

The morning after, Andrew says his goodbyes to Sam at the airport, even while she begs him not to leave. He acknowledges that she has changed his life but that he still has to fix his problems in LA before continuing the relationship.

In the final scene, we see Sam crying in a telephone booth just before Andrew unexpectedly returns, saying that "he doesn't want to waste any more of his life without her in it." Andrew wonders what is to be done next, and the two passionately kiss as "Let Go" by Frou Frou plays.