Heat stress negatively affects agricultural productivity, including milk production, growth, and reproduction. It also jeopardizes human and animal health, regionalizes food production, and compromises food security. Despite the broad, negative consequences of heat stress, interventions are largely limited to cooling, which fails to address underlying cellular dysfunctions. Our investigations have focused on heat stress-mediated changes to skeletal muscle in swine as this is an important agricultural tissue and because of its mass and energetic demands, it contributes greatly to regulation of systemic metabolism. We discovered oxidative stress and apoptotic signaling after only 2 h of heat stress, however, this appeared to be transient as it decreased linearly through 6 h despite persistent stress; a scenario suggesting activation of a corrective mechanism. Of interest, this transient dysfunction was associated with markers of increased autophagy and mitophagy, which would facilitate removal of damaged, pro-oxidant mitochondria. As heating continued through 12 and 24 h there was a reemergence of oxidative stress that corresponded with autophagic dysfunction and accumulation of autophagosomes. Indeed, following 24 h of heat stress we discovered increased markers of mitochondrial abundance, independent of biogenic signaling, which supports a failure of adequate removal. Similar changes were noted through 7 d of heat stress. Given these findings, mitochondrial injury and autophagic dysregulation appear to be key mediators of hyperthermic muscle dysfunction. Our future work will address the role of mito-protection and stimulation of autophagy during heat stress.