Significance In response to injury or disease, skeletal muscle has the capacity for regeneration and repair. Muscle regeneration is orchestrated by a population of stem cells called satellite cells that reside between the basal lamina and sarcolemma of muscle fibers. Upon muscle injury, activated satellite cells proliferate and undergo differentiation to recreate functional muscle tissue. In this work, we show that deletion of three members of the MEF2 family of transcription factors, MEF2A, C, and D, in satellite cells prevents muscle regeneration because of a failure of differentiation. Also, we identify a collection of muscle genes regulated by MEF2 in satellite cells. These findings provide a potential molecular inroad into the process of muscle regeneration through modulation of MEF2 activity.