Jamie Foxx voices Joe Gardner, a middle-aged music teacher at a New York public middle school, frustrated by his lack of success toward becoming a professional jazz club musician. He's offered full-time status with the school when another door of opportunity opens. A former student mentions that a legendary jazz saxophonist named Dorothea Williams is auditioning for a new pianist in her jazz ensemble. Nailing the audition, Joe is exuberant, failing to notice an open manhole before falling into it. He next finds himself disassociated with his body in an afterlife existence, a soul waiting for its final destination (dubbed "The Great Beyond").

With dreams unfulfilled, Joe desperately wants his life back, escaping his fate by posing as a mentor for new souls in a pre-life training area called "The Great Before." Joe's assignment is to direct a soul called 22 to find her spark that will keep her happy and productive before assuming her role in the living world. However, 22 is a special case, spending eons avoiding the process under other mentors (even Mother Teresa lost her cool with her). When Terry, the accountant for souls, notices one is missing, she pursues Joe after he escapes back to Earth to regain his life.