It's the 1940s and 8-year-old Dewey Cox (CONNER RAYBURN) lives in the shadow of his musically talented brother, Nate (CHIP HORMESS). While in a mock duel with him, Dewey accidentally cuts his brother in half, thus crushing their parents, Pa (RAYMOND J. BARRY) and Ma (MARGO MARTINDALE), with the former repeatedly telling Dewey from that point on that the wrong son died.
Years later and hoping to fill his late brother's shoes, 14-year-old Dewey (JOHN C. REILLY) is an aspiring singer-songwriter who wows the audience, including 12-year-old Edith (KIRSTEN WIIG), at a talent show. While that gets him kicked out from home due to playing "the devil's music," Dewey shoots to fame playing his song "Walk Hard" while accompanied by drummer Sam (TIM MEADOWS), guitarist Dave (MATT BESSER), and bass player Theo (CHRIS PARNELL).
Fame and fortune, however, soon lead Dewey astray, particularly from his now wife Edith and their growing number of kids back home. First, there are the drugs provided by Sam and others that get Dewey hooked on them. And then there's pretty backup singer Darlene Madison (JENNA FISCHER) who quickly wins his heart.
From that point on, and as the decades pass by and musical styles change, Dewey must contend with the effect those various personal demons, as well as the haunting memory of having accidentally killed his brother in the past, have on him and his career.