Rock star Aldous Snow (Russell Brand) releases an album and an accompanying single "African Child". The song and music video flops, is banned and called "the worst thing to happen to Africa since the apartheid" by NME. His girlfriend, Jackie Q (Rose Byrne), takes custody of their son, Naples, and leaves him; as a result, Aldous hits rock bottom by drinking and doing drugs excessively once again.
Meanwhile, in Los Angeles, Aaron Green (Jonah Hill) is a driven, idealistic young college graduate who works as a low-level talent scout at Pinnacle Records. He lives with his girlfriend, Daphne (Elisabeth Moss), a doctor in her internship, but they do not get to see each other often due to her heavy work schedule. Pinnacle Records has lost a lot of money, so the head of the company, Sergio Roma (Sean "Diddy" Combs), asks for ideas. Green proposes to have Aldous Snow play at the Greek Theatre in Los Angeles for the tenth anniversary of a particularly famous performance there. One month later, he sends Aaron to London to retrieve Aldous. Before leaving, Aaron visits sleep-deprived Daphne at her hospital to tell her that he'll be gone for a few days. She informs Aaron that she received a job offer at a hospital in Seattle, where she will have a less hectic work schedule. Aaron doesn't appreciate her insisting that they move to Seattle and leave their current jobs behind, and an argument ensues and leads to an implied break-up.
After retrieving Aldous from his apartment, Aaron tries desperately to control Aldous' rambunctious behavior, which causes them to miss several flights. They bar-hop across the city for several hours, leaving a trail of women and alcohol in their wake. Daphne calls him to apologize for the fight, but Aaron already believes that they had broken up. Throughout this partying, buttons on Aaron's cell phone (placed in his pocket) accidentally call his girlfriend, and his girlfriend overhears him partying with other women.
Once the two have made it to New York, they proceed to Aldous' Welcome Back performance on Today. Aaron receives word from Sergio to keep Aldous sober for his performance, and Aaron consumes all of Aldous' alcohol and marijuana on the way to the program. Minutes before the performance, Aldous realizes that he is unable to remember the lyrics to his favorite song, "African Child", shortly after Aaron had admitted to "African Child" being his least favorite Infant Sorrow song. Placing resentment and blame on Aaron, he sends him on a frenzy of drunk desperation in search of the lyrics. Aaron is unable to complete this task, and after the first few bars of "African Child", Aldous stops his band, and plays one of his older hits called "The Clap" to cheers and excitement from the audience. Aaron had also mentioned earlier that "The Clap" is his personal favorite.
While preparing to fly to Los Angeles, Aldous forces Aaron to smuggle heroin in his anus. During their travels and time in London and New York, Aaron learns that Aldous has become miserable and lonely, as he misses his son and has not seen any signs of genuine love from his own dad in years. Aaron shares his relationship troubles, and Aldous encourages him to enjoy his time in Los Angeles. Giving advice to Aldous, Aaron suggests he visits Jackie Q and his father and so the two make a stop in Las Vegas the night prior to the show to see Aldous's father. Sergio also arrives, wanting to help oversee the final proceedings. Sergio hooks up Aaron with a ditzy, sexually rambunctious girl named Destiny (Carla Gallo), who takes him to a room, shows him her pubic hair and rapes him. During this, his phone against accidentally calls his Daphne and she hears an out-of-context sample of what is going on. After Aaron tells Aldous that he has been raped, the other men laugh it off, and they encourage him to smoke a "Geoffrey", a joint which is eventually described as "a Neapolitan of drugs". Upon being told about the extra ingredients in the Geoffrey, Aaron panics and starts believing he is having a heart attack (he is actually just having a bad trip). Aldous' father repeatedly says that it is a heart attack, making the trip worse, whilst Aldous repeatedly attempts to calm Aaron down by telling him "to stroke the furry wall". Aldous has a fight with his father; Sergio jumps in the fight (also high on Geoffrey), and their tussle ends up setting the hotel room on fire. Aldous attempts to help Aaron with an adrenaline shot to the heart and they run out of the hotel, chased by Sergio who is then hit by a car.
Aldous and Aaron are driven to Los Angeles, where Snow visits Jackie Q. She has been sleeping with Metallica's drummer, Lars Ulrich (playing himself) - and is apparently engaged to him, and confesses to Aldous that Naples is not actually his biological son. This depresses him even further. Meanwhile, Aaron goes to his home to apologize to Daphne. The are interrupted when Aldous Snow comes to their house and becomes involved in the conversation. Snow proposes that he, Aaron, and Daphne engage in a threesome because Aaron had been with other women during his time with Aldous Snow. During the threesome, resentful Aaron angrily decides to kiss Aldous, eventually ending the threesome. Daphne feels horrible about the threesome, and storms out of the room. Aaron angrily tells Aldous to go, and criticizes Aldous' overall mental state.
Instead of preparing for his show, Aldous goes to the rooftop of the Standard Hotel in Downtown Los Angeles, and calls Aaron, threatening to jump. Aaron rushes to the hotel rooftop pool in an attempt to coax Aldous down from the roof. Aldous attempts to jump down to the pool instead of killing himself, and accidentally shatters his arm against the poolside. Aldous tells Aaron that he is lonely and feels unconnected to people. Aaron tells Aldous that he is trying too hard, and that thousands of fans love him and are waiting just to see his face. Aldous, inspired by Aaron's words, decides to go and perform at the Greek theatre. Aaron tries to take him to the hospital, but Aldous insists on making it to his performance at the Greek. Upon his arrival, Sergio attempts to offer Aaron drugs to give to Aldous to ease the pain he is in. Aaron angrily refuses and quits his job on the spot. He walks stage-side with Aldous, trying to convince him one last time to go to the hospital instead. However, Aaron sees how happy Aldous is performing and allows him to continue while he himself goes home and reconciles with his girlfriend. Months later in Seattle (where Aaron and his girlfriend have moved), a healthier and sober Aldous Snow has returned to fame with a single produced by Aaron based on events from their night in Las Vegas, performing on the VH1 Storytellers program.