Apoptosis is a highly conserved type of cell death that plays a critical role in tissue homeostasis and disease-associated processes. Skeletal muscle is unique with respect to apoptotic processes, given its multinucleated morphology and its apoptosis-associated differences related to muscle and (or) fiber type as well as mitochondrial content and (or) subtype. Elevated apoptotic signaling has been reported in skeletal muscle during aging, stress-induced states, and disease; a phenomenon that plays a role in muscle dysfunction, degradation, and atrophy. Exercise is a strong physiological stimulus that can influence a number of extracellular and intracellular signaling pathways, which may directly or indirectly influence apoptotic processes in skeletal muscle. In general, acute strenuous and eccentric exercise are associated with a proapoptotic phenotype and increased DNA fragmentation (a hallmark of apoptosis), whereas regular exercise training or activity is associated with an antiapoptotic environment and reduced DNA fragmentation in skeletal muscle. Interestingly, the protective effect of regular activity on skeletal muscle apoptotic processes has been observed in healthy, aged, stress-induced, and diseased rodent models. Several mechanisms for this protective response have been proposed, including altered anti- and proapoptotic protein expression, increased mitochondrial biogenesis and improved mitochondrial function, and reduced reactive oxygen species generation and (or) enhanced antioxidant status. Given the current literature, we propose that regular physical activity may represent an effective strategy to decrease apoptotic signaling, and possibly muscle wasting and dysfunction, during aging and disease.