The film starts with Johnny "Drama" Chase (Kevin Dillon), Eric "E" Murphy (Kevin Connolly), and Sal "Turtle" Assante (Jerry Ferrara) riding a motorboat to a yacht party for their buddy Vincent Chase (Adrian Grenier). Vince has just been separated from his wife after nine days of marriage and is already dating Nina Agdal. The guys talk about a new project for Vince. He calls up his former agent-turned-studio head Ari Gold (Jeremy Piven). Ari offers Vince the project, but Vince says that he wants to direct the film too. Ari is left silent.
After an opening credits sequence (not unlike that of the TV series), we see a segment from Piers Morgan eight months later, detailing Vince's directorial debut, "Hyde", which is a new take on "Jekyll and Hyde". Vince has cast Drama in a pivotal supporting role. The segment also adds that E is still managing Vince while Turtle is still his driver. Ari is obviously nervous about having allowed Vince, a big Hollywood actor, to go ahead and take on such a big project for his first-time directing gig. Drama, meanwhile, is confident that he will nab himself an Oscar nomination.
The film's production goes over-budget by $15 million. The guys head to the studio to meet with Ari so Vince can ask him for more in addition to the $100 million Ari already gave Vince. Ari doesn't want to do it because he'll have to involve financiers from Texas, but Vince is certain that he needs it to fully complete his vision.
As the guys leave the studio, Turtle catches a glimpse of Ronda Rousey. He gets excited and follows her, hoping she will remember him from the one time they met. She stops her car in the middle of the street and grabs a wrench to hit Turtle's car until she recognizes him and Vince, noting that Turtle used to be fat.
E meets up at the OB/GYN with his ex-girlfriend Sloan (Emmanuelle Chriqui), who is close to giving birth. He meets T.I. in the waiting room, who is pissed that he's about to have another baby. E is also currently seeing a new girl named Melanie (Sabina Gadecki), though he hasn't told Sloan about her. She finds out when she sees a text from her that says she wants E's cock.
Ari is in Texas to meet with the financiers. He chats on FaceTime with his former assistant Lloyd (Rex Lee). Lloyd is getting married and wants Ari to give him away because he has a sour relationship with his dad. Ari groans and hangs up as he pulls up to the home of the financiers, Larsen McCredle (Billy Bob Thornton) and his doofus son Travis (Haley Joel Osment). The two are hesitant in giving Ari more money, but Ari is confident in Vince's work and persuades Larsen to give up the money. He sends Travis back with Ari to ensure things go well.
After the movie's rough cut is complete, Vince hosts a screening party, with celebrity guests like Gary Busey, Clay Matthews, Andrew Dice Clay, and Bob Saget, who asks Vince to have sex with his daughter's friends so he won't have to. Drama chats with Jon Favreau for a part in another "Iron Man" movie, which Favreau declines. Ronda also shows up to hang out with Turtle. They walk in on E, hopped up on molly water, having sex with a girl he just met named Paula (Christine Donlon). Ari is upset that he's the only one that didn't get an invite, so he heads to the party himself to view the film anyway. Travis tags along and gets excited when he sees Vince with Emily Ratajkowski, as he has a huge crush on her. He introduces himself to her and comes off like a fool. A nervous Vince backs out and tells everyone that the projector broke, so he saves face by introducing the guests to Pharrell and gets him to perform. He gives Ari a DVD of the film for his own personal viewing.
Ari watches the film at home. We see a bumping party in a tunnel where Vince, as the main character, plays the DJ. The cops show up to bust the party, until Vince throws everyone at the party a container of some sort. One person hurls a Molotov cocktail at the cops. Vince takes the serum and morphs into the film's Hyde persona. It then cuts to the next day where Ari has left Vince and the guys with a sweet new ride to show that he absolutely loved the movie, and he even gets E a mini-scooter as a gag. Ari drives to the studio to find Travis parked his car in Ari's spot. Ari leaves his car in front of Ed O'Neill's car, to the actor's dismay. Ari confronts Travis, who tells him that while he liked the movie, he did not like Drama's performance, and he demands that Vince cut Drama from the film.
Turtle continues his pursuit of Ronda, but Drama thinks she is only talking to him to expand her brand. He meets with her and starts talking business, only to discover that Ronda actually is interested in him and cooked a meal for them, but she is upset at his behavior and orders him to leave.
E joins Sloan at a Lamaze class and admits he still has some interest in her. She invites him to join her for sex until he admits he had sex with two women in the same day. Sloan leaves and E gets a call from Melanie, who says she is pregnant. She tells him to meet her at a restaurant. He walks there until Turtle and Drama spot him and take him there. Paula finds him and sits with him, suggesting she may have given him an STD. Melanie arrives and sits to argue with Paula, until it turns out they know each other and orchestrated the whole thing to see if E was a typical L.A. douchebag. Knowing that Melanie isn't pregnant and that Paula doesn't have a disease, E leaves in high spirits.
Ari joins his wife (Perrey Reeves) at an anger management session with Dr. Marcus (Nora Dunn). The couple sees Kelsey Grammer leaving, swearing profusely. Ari has tried to keep his anger under control, but all the pressure from the movie is getting to him. He takes a phone call in the middle of the session to learn that Travis has locked himself in the studio and has kept everyone else out. Ari furiously punches a framed picture of a cat and continues with the meeting.
Vince goes to the studio to try and get Travis to come out. He is approached by Mark Wahlberg and his own entourage as Ari shows up to tell Vince that Travis wants to cut Drama out of the picture. Mark says it's messed up and he wouldn't cut any of his family out of his stuff. Vince realizes he has to break the news to Drama himself.
Drama is engaging in an affair with a woman he hooked up with at the screening party. They're about to get kinky on their phone cameras until the girl's boyfriend comes in and threatens Drama.
Ari's assistant (Scott Mescudi) finds Ari during a meeting and tells him that the studio CEO John Ellis (Alan Dale) wants Ari to see him in his office. He retorts that Ellis should see him in his own office, forcing Ari to head to his office through the studio. He passes David Spade, who is upset that they're releasing "Hyde" on a date where one of his movies is coming out, along with Jessica Alba, who wants Ari to greenlight her passion project and also expresses her disgust at the director of her current project that is taking pictures of her ass. Ari gets to his office before Ellis does and plays hardball regarding the movie. However, Ellis still takes him off the project and replaces him.
Vince finds his friends and tells them about their problem. Without saying a word, Drama realizes that HE is the problem. This sends him into a depression. He's drinking in the car on the way to a meeting with Travis. Vince and E speak with Travis, who admits he hated Vince in the movie. This throws everybody for a loop. Ari realizes something is up. He goes to meet with Travis, and realizes it's something personal, but he doesn't know what. Over lunch later, Vince confesses to the guys he's dating Emily Ratajkowski, and the guys realize that's why Travis is pissed.
Drama goes to another audition, only for the casting directors to not pay attention to him because they see a viral video of Drama masturbating furiously, which the girl's boyfriend uploaded in retaliation. Drama is unable to escape the mockery wherever he goes.
The guys join Turtle as he goes to the gym to apologize to Ronda for how he acted. She challenges him to a cage match to prove he really wants to go out with her. Turtle asks if 30 seconds will get him a date with her, to which Ronda says she'll have sex with him if he lasts a full minute. Ronda knocks Turtle on his ass and snaps his arm, right as the clock ticks 30 seconds.
Ari flies to meet with Larsen, Ellis, Travis, and his old friend Dana Gordon (Constance Zimmer). He confronts the McCredles and says that the only reason Travis is slamming the movie is because he hates Vince, and it's because he's jealous of the time he spends with Emily. Apparently, Travis stayed outside her house one night to see if Vince would show up. Larsen is disappointed in his son and orders Travis to stay outside for the meeting. Ari gives Larsen a DVD of the movie, with Dana adding that she thinks it's amazing. Larsen says he trusts the studio because they do good work, but he won't give them anymore money unless Ari is fired. He says it's because he treated Travis poorly. He tells Ari that even if his son is a buffoon, he still wishes people would at least pretend to respect him. This seems to resonate with Ari, who realizes he screwed up.
Sloan's waters break, and the guys go to the hospital for the birth of E's child. E tells Sloan that he still loves her. She gives birth to a healthy baby girl that they name Ryan Murphy (yes, after THAT Ryan Murphy). Drama forgets about his woes once he learns that E's daughter was born. He joins the gang at the hospital to celebrate. While there, Vince gets a phone call from Piers Morgan asking for a comment about the recent resignation of Ari as studio head. Ari arrives at the hospital room at the same time.
On their way out of the hospital, Ari explains his resignation as a way to save dignity, as they were going to fire him anyways. He explains that he turned down a hefty severance package in exchange for a share of the profits from Vince's movie. He believes in the movie, and is proud of Vince and his entourage. We move to months later at the Golden Globe Awards, where we learn from Maria Menounos and Matt Lauer that "Hyde" is a worldwide box office success, and it's garnered 4 nominations, including Best Picture and two acting nominations for Vince and Drama. Ari is interviewed and says he is up for another job at another studio, so he's doing just fine. As the show starts, Vince, E, Drama, Turtle, and Ari all head in together.
Before the end credits start, Mark is announcing the winner for Best Supporting Actor. To his surprise, the winner is Drama. Drama is stunned, and he goes to accept the award. He is silent for a moment before yelling, "VICTORY!!!" His pals and every other guest cheer for him.
In a mid-credits sequence, Ari gives Rex away at his wedding, with all the guys in attendance. During the reception, they get together for a picture. During this time, Turtle pitches the idea of a movie detailing how Vince and his crew came from nothing and made something out of themselves. Ari says it's the dumbest idea ever. Turtle retorts that maybe it could be made into a TV series.