Composer Peter Bretter (Jason Segel) is in a five-year relationship with actress Sarah Marshall (Kristen Bell), who stars in a CSI-like television show titled Crime Scene: Scene of the Crime. One day, as Peter stands stark naked in their apartment, Sarah announces that she is breaking up with him. Devastated, and unable to banish his grief through one-night stands, Peter takes a trip to Hawaii. However, the vacation is ruined when he learns that Sarah and her new rock star boyfriend Aldous Snow (Russell Brand) are also guests of the resort. Taking pity on him, hotel concierge Rachel (Mila Kunis) offers him an expensive suite for free in exchange for cleaning up the room himself.
Alison Scott (Katherine Heigl) is a career-minded woman who has just been given an on-air role with E! and is living in the pool house with her sister Debbie's (Leslie Mann) family. Ben Stone (Seth Rogen) is laid-back and sardonic. He lives off funds received in compensation for an injury and sporadically works on a celebrity porn website with his roommates (Jay Baruchel, Jonah Hill, Jason Segel and Martin Starr), in between smoking marijuana or going off with them at theme parks such as Knott's Berry Farm. While celebrating her promotion, Alison meets Ben at a local nightclub. After a night of drinking, they end up having sex. Due to a misunderstanding, they don't use protection: Alison uses the phrase "Just do it already" to encourage Ben to put the condom on, but he misinterprets this to mean to dispense with using one. The following morning, they quickly learn over breakfast that they have little in common and go their separate ways, which leaves Ben visibly upset.
Seth (Jonah Hill) and Evan (Michael Cera) are two high school seniors who lament their virginity and poor social standing. Best friends since childhood, the two are about to go off to different colleges, as Seth didn't get accepted into Dartmouth like Evan. After Seth is paired with Jules (Emma Stone) during Home-Ec class, she invites him to a party at her house later that night. Later, Fogell (Christopher Charles Mintz-Plasse) comes up to the two and reveals his plans to obtain a fake ID during lunch. Seth uses this to his advantage and promises to bring alcohol to Jules' party. Fogell's fake ID is met with derision by Seth and Evan, as it states that Fogell's name is simply "McLovin". After contemplating their options, Seth decides they have no choice but to have Fogell buy the alcohol with his fake ID. Fogell goes in and successfully buys the alcohol, but is interrupted when a robber enters the store, punches him in the face, and takes money from the cash register.
Dewey Cox begins his quest for stardom in Springberry, Alabama in 1946. While playing with his brother Nate, Dewey accidentally cuts his brother in half at the waist with a machete. This leads Dewey's father to frequently repeat the phrase "The wrong kid died" throughout the film. The trauma causes Dewey to lose his sense of smell – "you've gone smell blind," states Dewey's mother. After his brother's death is announced by a physician making a housecall, Dewey's mother sends him to the local store to buy some butter and a candle. There, he meets a blues guitarist, who lets Dewey play his guitar. Dewey is a natural.
Ricky Bobby (Will Ferrell) is a NASCAR driver who wants to go fast. While he was working on the pit crew of Dennit Racing driver Terry Cheveaux (Adam McKay), Ricky replaces him and ends up finishing in third place, despite starting mid-race in last place. Ricky quickly soars to the top of NASCAR by achieving his fame and fortune at Dennit Racing and meeting his future wife, Carly (Leslie Bibb). Ricky eventually persuades Dennit to field an additional car and arranges to have his best friend, Cal Naughton, Jr. (John C. Reilly), on his team. While he and Cal are on top of the racing world, Ricky challenges his flamboyant French Formula One archrival, Jean Girard (Sacha Barone Cohen), who outperforms him on the track and becomes Dennit Racing's next top driver. Desperate to regain his dominance, Ricky pushes himself too hard during the race at Charlotte Motor Speedway and ends up going airborne, barrel-rolling several times.
Andy Stitzer (Steve Carell) is a 40-year-old virgin who is involuntarily celibate. He lives alone, collects action figures, plays video games, and his social life seems to consist of watching Survivor with his elderly neighbors. He works in the stockroom at an electronics store called SmartTech. When a friend drops out of a poker game, Andy's co-workers David (Paul Rudd), Cal (Seth Rogen), and Jay (Romany Malco) reluctantly invite Andy to join them. At the game (which he wins, due to playing online poker constantly), when conversation turns to past sexual exploits, Andy desperately makes up a story, but when he compares the feel of a woman's breast to a "bag of sand", he is forced to admit his virginity.
Phil Weston (Will Ferrell), is an average person who had to endure his father Buck Weston's (Robert Duvall) over-competitiveness throughout his childhood, an upbringing which has left permanent mental scars. Now middle-aged and married, with a young son named Sam, Phil runs a small vitamin store, while Buck operates a local chain of sports stores.
In 1974, Ron Burgundy (Will Ferrell) is the famous anchorman for a local San Diego television station, fictional KVWN channel 4. He works alongside his friends on the news team: lead field reporter Brian Fantana (Paul Rudd), sportscaster Champion "Champ" Kind (David Koechner), and intellectually disabled chief meteorologist Brick Tamland (Steve Carell). Station director Ed Harken (Fred Willard) informs the team that they have maintained their long-held status as the highest-rated news program in San Diego, leading them to throw a wild party, where Ron unsuccessfully tries to pick up a beautiful, blonde woman (Christina Applegate). Ed later informs the team that they have been forced to hire Veronica Corningstone, the same woman whom Ron tried to pick up. After a series of unsuccessful attempts by the team to seduce her, she finally relents and consents to a "professional tour" of the city with Ron, culminating in a sexual relationship. Despite agreeing to keep the relationship discreet, Ron announces it on air.