Besides functioning as thermosensors, transient receptor potential vanilloid 1 (TRPV₁) channels play a pivotal role in ischemia–reperfusion injury. Transient receptor potential vanilloid 1 channel activation attenuates ischemia–reperfusion-induced injury in various organs including the heart, lungs, kidneys, and the brain. Transient receptor potential vanilloid 1 channels are expressed on the sensory neurons innervating the myocardium, ventricles of the heart, epicardial surface of the heart, endothelial cells, and the vascular smooth muscle cells. During ischemic conditions, activation of TRPV₁ channels on the perivascular nerves stimulates the release of calcitonin gene-related peptide and substance P to produce cardioprotection. Furthermore, TRPV₁ channel activation reduces the generation of free radicals and inflammatory cytokines, inhibits neutrophil infiltration, and enhances the production of anti-inflammatory cytokines to reduce ischemia–reperfusion-induced tissue injury. The present review describes the potential involvement of TRPV₁ channels and the signaling cascade in attenuating ischemia–reperfusion injury in various organs.