Irisin, an exercise-induced myokine, is known to be able to regulate bone metabolism. However, the underlying mechanisms regarding the effects of irisin on senile osteoporosis have not been fully elucidated. Here, we demonstrated that irisin can inhibit bone mass loss and bone microarchitecture alteration in senile osteoporosis mouse model. In addition, irisin has effects on bone remodeling that is in favor of bone formation. Remarkably, irisin induced autophagy in osteocytes demonstrated by increased LC3-positive osteocytes, and increased autophagy-related genes and proteins. In vitro analysis revealed that Irisin can prevent mitochondrial oxidative damage. Furthermore, irisin can obviously induce osteocyte mitophagy and increased phosphorylation of Ampk and Ulk1. Inhibition of Ampk signaling recapitulated the biological effect of irisin loss, accompanied by the markedly lower expression of Ulk1. Taken together, our findings show that irisin reduces age-related bone loss by inducing osteocyte mitophagy via Ampk-dependent activation of Ulk1.