Mitochondrial unfolded protein response (UPR) is a mitochondrial stress response that activates the transcriptional program of mitochondrial chaperone proteins and proteases to keep protein homeostasis in mitochondria. Ischemia-reperfusion injury results in multiple severe clinical issues linked to high morbidity and mortality in various disorders. The pathophysiology and pathogenesis of ischemia-reperfusion injury are complex and multifactorial. Emerging evidence showed the roles of UPR signaling in ischemia-reperfusion injury. Herein, we discuss the regulatory mechanisms underlying UPR signaling in C. elegans and mammals. Furthermore, we review the recent studies into the roles and mechanisms of UPR signaling in ischemia-reperfusion injury of the heart, brain, kidney, and liver. Further research of UPR signaling will potentially develop novel therapeutic strategies against ischemia-reperfusion injury.