Objective(s): This research was designed to determine the role of irisin in lipopolysaccharide (LPS)-induced endometritis in female mice. Materials and Methods: Animals were randomly assigned into sham, sham + irisin, LPS, LPS + irisin (0.1, 1, 10 mu g/kg), and LPS + irisin + compound C groups. Histological features and expression of AMPK, NF-kappa B, inflammatory mediators, and oxidative stress markers were compared among different groups. Results: The results showed that LPS resulted in obvious uterus damage, meanwhile, the inflammatory mediators (COX-2, iNOS, IL-1 beta, IL-6, and TNF-alpha), as well as NF-KB in the uterine tissue, were significantly increased and the level of adenosine monophosphate-activated protein kinase (AMPK) was reduced. Nevertheless, pretreatment with irisin reversed the phenomena caused by LPS. Interestingly, compound C (AMPK inhibitor) abolished irisin's effects on the uterus, which suggested that irisin's beneficial function was achieved through regulating the AMPK-NF-kappa B pathway. Moreover, LPS-induced alterations of oxidative factors (MnSOD, GSH, and MDA) were reversed significantly by pretreatment with irisin. This data indicated irisin's beneficial function was also related to antioxidation besides anti-inflammation. Conclusion: Our study implies that irisin is a potential therapeutic agent for endometritis.