Sterile inflammation is an essential factor causing hepatic ischemia/reperfusion (I/R) injury. As a critical regulator of inflammation, the role of monocyte chemoattractant protein-induced protein 1 (MCPIP1) in hepatic I/R injury remains undetermined. In this study, we discovered that MCPIP1 downregulation was associated with hepatic I/R injury in liver transplant patients and a mouse model. Hepatocyte-specific Mcpip1 gene knockout and transgenic mice demonstrated that MCPIP1 functions to ameliorate liver damage, reduce inflammation, prevent cell death, and promote regeneration. A mechanistic study revealed that MCPIP1 interacted with and maintained hypoxia-inducible factor 1 alpha (HIF-1 alpha) expression by deubiquitinating HIF-1 alpha. Notably, the HIF-1 alpha inhibitor reversed the protective effect of MCPIP1, whereas the HIF-1 alpha activator compensated for the detrimental effect of MCPIP1 deficiency. Thus, we identified the MCPIP1-HIF-1 alpha axis as a critical pathway that may be a good target for intervention in hepatic I/R injury. (HEPATOLOGY 2018;68:2362-2379).