Nick O’Leary (Michael Cera), a teenager from Hoboken, New Jersey, is heartbroken after his girlfriend, Tris (Alexis Dziena), breaks up with him. His mates in the queercore band The Jerk-Offs (of which Nick is the only heterosexual member), Thom (Aaron Yoo) and Dev (Rafi Gavron), finally convince him to leave the house to perform at a club later that night only because his favorite band, the legendary publicity-shy indie band "Where's Fluffy?", is performing somewhere in New York City that evening.
Norah Silverberg (Kat Dennings) and her best friend, Caroline, (Ari Graynor) attend the same high school as Tris. Norah and Tris dislike each other as Norah is smart and motivated, having been accepted into Brown University, while Tris is a self-interested brat. Tris shows Norah and Caroline a mix CD Nick has made for her and throws it away. Norah takes the mix CD out of the garbage, having been recovering the discarded mix CDs for a while. That night, they all end up at Arlene's Grocery on Manhattan's Lower East Side where The Jerk-Offs are playing. While performing, Nick sees Tris in the audience with another guy. Meanwhile, Norah eyes Nick on stage. Thom and Dev meet Lethario (Jonathan B. Wright). Norah asks Nick to be her boyfriend for five minutes to prove to Tris that she is going out with someone. Norah kisses Nick, not knowing that Nick is Tris' ex, and incites Tris' jealousy. Caroline gets drunk and Norah wants to take her home, but Nick's band-mates, who see Norah as a potential girlfriend for Nick, give Norah some clothes they know that Nick likes and then offer to take Caroline home so she can ride with Nick. While Nick and Norah search for "Where's Fluffy?", Caroline wakes up in the back of the van and overhears Thom and Dev having a graphic sexual conversation. (They are actually just trying to come up with a new name for their band). Fearing that they are talking about raping her, she runs away. Nick and Norah travel around, discovering they both love "Where's Fluffy?". Nick brings up Tris' name, to Norah's dismay, and they decide to call it a night after having an argument. Nick gets a call from his band-mates telling him that they lost Caroline. Nick tells Norah about Caroline and they meet with the band-mates to try to find her. After no luck finding Caroline, they hope that she is already at the "Where's Fluffy?" concert. They all go to a club to see if the band and Caroline are there. Nick decides to show he is interested in Norah and starts dancing with her only to be interrupted by Norah's ex, Tal (Jay Baruchel).
It turns out to be a show for another artist, "Are You Randy", and everyone (except for one fan) leaves. While trying to find Caroline, they are followed by Tris who wants to get back with Nick. Tris tries to convince Norah that Nick is not for her and taunts her with the knowledge of her secret that she has never had an orgasm. Tris gets a phone call from Caroline, who tells Norah that she has "found Jesus" and an altar boy without pants. Norah tells Nick and the band about the information she got from Caroline, and luckily Thom and Dev know where she is. They find Caroline on stage drunk at a gay cabaret dressed as a Christmas tree.
On the way back home, Nick sees Tris waiting on the hood of his Yugo and decides to confront her. Before he leaves, Norah stops him to say how nice it was to meet him. Nick simply leaves without a response. Upset, Norah calls Tal. When Norah meets up with him, she realizes that he wants to use her because her father is a music producer. Tal wants to see if his band can make a deal with Norah's father. When the check arrives for Tal and his friends' drinks, he asks Norah if she can "take care of it" because of her connections from her father's reputation. She agrees, but instead she tells the waitress that there was a miscalculation and to increase the tab tenfold by adding a zero to the end; Norah then leaves.
As Nick confronts Tris, she shows how she wants him back and asks for a ride home. Tris asks Nick to stop by the river, where she tries to seduce him to take her back by putting his hand on her breast. She seductively dances in front of the car to "You Sexy Thing" by Hot Chocolate, but as she dances, Nick reminisces about Norah and the night's events and decides that he is over Tris. He drives away, leaving Tris behind.
Nick calls Norah, apologizing for leaving, and she agrees to meet up with him again. They both decide to go somewhere no one they know will find them. Norah offers to drive, and turns out to be a reckless driver, who crashes his car into a fire hydrant. They arrive at Electric Lady Studios, a music studio owned by her father. Nick is fascinated at the equipment and history of the studio. Norah asks Nick to play something in the recording room. Before he starts singing, she joins him and the two start to kiss. They collapse onto a nearby sofa and the camera cuts to the recording equipment, which is picking up the two of them talking, with some suggestive remarks and ends with Norah having an orgasm. She gets a text message from Caroline that they found Fluffy. The two decide to go, only to find Tal and Tris already there. Tris cannot understand why Nick will not take her back, and Tal wants the same answer from Norah. Tal pulls Norah away from Nick. Nick and Tal start shoving each other until Lethario finally intercedes and headbutts Tal. Nick and Norah share a smile, grab hands and leave. They reach Pennsylvania Station. As they head for the train, Norah questions Nick about missing the concert, but Nick says he does not care. Norah steps towards him as they share a kiss on the escalator as the sun rises over New York City.