Increasing evidence indicates that prolonged fat-rich diet (HFD) ingestion is a predisposing factor for metabolic disorder-associated system inflammation and oxidative stress injury, which contributes to the occurrence of non-alcoholic fatty liver disease (NAFLD). NACHT, LRR and PYD domains-containing protein 3 (NLRP3)-mediated inflammatory infiltration was determined to participate in NAFLD. X-linked inhibitor of apoptosis protein (XIAP) was recently confirmed as an essential regulator for apoptosis in cells. However, the role of XIAP in HFD-induced NAFLD is still not understood. Here, XIAP was characterized with respect to HFD-induced NLRP3 inflammasome activation and reactive oxygen species (ROS) generation in vivo and palmitate (PA)-treated cells in vitro. After HFD administration, hepatic injury was confirmed via histological assessment (grading and staging of NAFLD) and biochemical parameters, oxidative stress, and reduced antioxidant activity. Up-regulated hepatic dysfunction were further indicated by elevated dyslipidemia, lipid accumulation, and decreased fatty acid β-oxidation associated gene expression. Moreover, in the absence of XIAP, NLRP3 signaling activated by HFD-triggered oxidative stress was up-regulated, accompanied by reduction in antioxidants including HO-1, NQO-1, GST, SOD and Nrf2 activity. The detrimental effects of XIAP blocking on hepatic steatosis and related pathologies were also confirmed in PA-treated mouse liver cells. In contrast, overexpression of XIAP by transfection in vitro restrained PA-stimulated hepatic steatosis by suppression of oxidative stress, NLRP3 related inflammatory response, and impairment of Nrf2 activity, further alleviating abnormal metabolic disorder associated NAFLD. Taken together, the present study helped to elucidate how HFD-induced hepatic steatosis was regulated by XIAP, possibly via the inhibition of NLRP3 signaling and oxidative stress injury.