At age 14, a performance at a local talent show becomes a seminal moment as the crowd reacts to his innocuous song, “Take My Hand,” with wild abandon. Because of this, Dewey (now played by John C. Reilly) is forced to leave town with his new girlfriend, Edith (Kristen Wiig), to escape the scornful eye of Pa Cox and the harsh life of Springberry. Heading out into the world to pursue the promise of his music, Dewey and Edith soon marry and have a gaggle of children while Dewey’s dreams of musical glory languish amid the diapers and unpaid bills as he continues to write songs that may never be heard.

While sweeping floors as the only white man in an African-American jazz club, Dewey gets his chance to perform when the headliner is unable to play one evening. Watching his triumphant performance of the blues standard “Mama, You Got to Love Your Negro Man” are record executives L’Chai’m (Harold Ramis), Mazeltov (Phil Rosenthal), and Schmendrick (Martin Starr), who arrange for Dewey to record a song at the famous Planet Records studio. There, Dewey performs “Walk Hard,” the song that would become his signature hit. He gains not only a recording contract but his first and only backing band: drummer Sam (Tim Meadows), whom he first met at the jazz club; guitarist Dave (Matt Besser); and bass player Theo (Chris Parnell).

The turbulent musical landscape of the 1950s becomes Dewey’s playground. With a rapturous public hungry for rock ‘n’ roll, Dewey climbs the stairway to stardom alongside such icons as Elvis Presley… but the more money he makes, the more his marriage to Edith suffers. Saddled with Dewey’s many children as well as his growing menagerie of exotic pets (including a chimp, a giraffe, and a camel), Edith pays the price for every hit single, road trip, and house purchase.

Life on the road proves to be Dewey’s heaven and hell. Now a proven rock ‘n’ roll star, he succumbs to the evils of backstage life: alcohol, drugs, and dalliances. However, Dewey meets his match when Darlene Madison (Jenna Fischer) becomes his new background singer. As beautiful as she is pious, Darlene refuses to sleep with Dewey until they are wed. Dewey quickly makes Darlene the second Mrs. Cox – forgetting, of course, that he is still married to the first Mrs. Cox. When Edith discovers Dewey with Darlene, Dewey soon finds himself divorced from his first wife and estranged from his second.