Cerebral ischemia is a leading cause of death and long-term disability in the world. Multiple signaling pathways play essential roles in the process. Therefore, identifying the unknown important modulators of these pathways may supply promising therapeutic targets for the treatment of cerebral ischemia. Ubiquitin-specific protease 10 (USP10) is a member of the ubiquitin-specific protease family of cysteine proteases with enzymatic activity to cleave ubiquitin from ubiquitin-conjugated protein substrates, and is involved in multiple pathologies. However, the effects of USP10 in cerebral ischemia-reperfusion (I/R) injury remain unclear. Here, we reported that USP10 expression was markedly decreased in wild type (WT) mice after cerebral I/R injury. USP10 knockout (KO) mice showed significantly elevated infarct size and the neurological deficit score after cerebral I/R operation. USP10 deletion also promoted inflammatory response in ischemic penumbra of cortical regions by further accelerating nuclear factor kappa B (NF-kappa B) signaling pathway. In addition, apoptosis was markedly induced in USP10-knockout mice after cerebral I/R injury compared to the WT mice, The c-Jun N-terminal kinase-mitogen-activated protein kinase (JNK-MAPK) signaling induced by cerebral I/R injury was further aggravated in USP10-KO mice. Finally, USP10 was found to display protective effects against cerebral I/R injury through direct interaction with transforming growth factor beta-activated kinase 1 (TAK1). Thus, USP10 might be a protective factor in cerebral I/R injury. Modulation of USP10/TAK1 might be a promising strategy to prevent this pathological process. (C) 2019 Published by Elsevier Inc.