It's 1944 Arkansas and J.R. (RIDGE CANIPE) and Jack Cash (LUCAS TILL) are two brothers who are obviously close and love music, despite having an overbearing and mean father in the form of Ray Cash (ROBERT PATRICK). When Jack is accidentally killed in an accident, Ray claims that the devil is responsible and took the wrong son, thus forever affecting how young Johnny views his father.
Years later, and after serving a stint in the Army, Johnny (JOAQUIN PHOENIX) is married to Vivian (GINNIFER GOODWIN), has a child with her, and isn't very good at being a door to door salesman in Memphis, Tennessee. He then happens upon a small recording studio run by Sam Phillips (DALLAS ROBERTS) who he convinces to let him, guitarist Luther Perkins (DAN JOHN MILLER) and bassist Marshall Grant (LARRY BAGBY) audition. Sam isn't impressed and says that their gospel music won't sell, asking if they have anything else.
When Johnny starts playing and singing a song he penned while in the service, he creates a sound that soon makes him a sensation. It's not long before he's touring with the likes of other up and coming stars such as Elvis Presley (TYLER HILTON) and Jerry Lee Lewis (WAYLON MALLOY PAYNE), but Johnny is most interested in June Carter (REESE WITHERSPOON) who's been a performer most of her life.
While on tour with her and the others, Johnny starts falling for her, but various conditions and events prevent anything from blossoming. And that mainly pertains to Vivian who's back home and upset with Johnny over never being around for her and their kids, as well as his growing dependency on prescription medication. With that affecting his career, Johnny must choose what to do with his life as he continues to pursue his music career as well as June's heart.