Ubiquitin-specific protease 22 (USP22), a potential marker of cancer stem cells, significantly influences stem cell fate choices. However, its functions in neural stem cells (NSCs) and adult neurogenesis, especially following traumatic brain injury (TBI), remain only partially understood. Here, we found that aberrant USP22 expression could affect NSC proliferation and stemness maintenance, as assessed by the generation of neurospheres, cell counting kit-8 (CCK-8) and immunofluorescence staining in vitro. Moreover, USP22 depletion promotes the differentiation of NSCs, both in vitro and in vivo. In contrast, USP22 overexpression inhibits NSC differentiation into neurons. Interestingly, our data showed that USP22 promotes the proliferation but inhibits the differentiation of NSCs in the dentate gyrus (DG)of the hippocampus soon after TBI. The Morris water maze (MWM) test was adopted to evaluate neurological function, which confirmed that USP22 could improve the learning and memory capacity that was already compromised following TBI. Overall, this study uncovers a potentially novel regulatory role of USP22 in the proliferation and differentiation ability of NSCs, contributing to the hippocampus-dependent cognitive function of TBI mice and may be a novel target for future therapeutic approaches.Copyright © 2022 IBRO. Published by Elsevier Ltd. All rights reserved.