BACKGROUND: Traumatic brain injury (TBI) is a major cause of neurological disability, and current treatments have limited effectiveness. Recent studies have emphasized the potential of exosomes derived from umbilical cord mesenchymal stem cells (UC-MSCs-Exo) in TBI treatment, but the molecular mechanisms underlying their therapeutic effects are not fully understood. METHODS AND RESULTS: In this study, UC-MSCs-Exo was isolated using ultracentrifugation and intraventricularly injected to TBI rat model. The neurofunctional motor function of the rats was evaluated using the modified neurological severity score (mNSS), and the activation of microglia was assessed through immunofluorescence detection of IBA1 expression levels. Additionally, we established an in vitro neuroinflammatory model using BV2 microglia to investigate the effects of UC-MSCs-Exo and miRNA-21. Our findings indicate that UC-MSCs-Exo promote neurological recovery in TBI rats and inhibit excessive microglia activation. Furthermore, UC-MSCs-Exo highly expresses miRNA-21 and inhibited the proliferation, migration, and release of inflammatory mediators of BV2 microglia by transporting miRNA-21. CONCLUSIONS: The present study suggests that the promotion of neurological recovery in TBI rats by UC-MSCs-Exo may be attributed to the inhibition of excessive microglia activation through miRNA-21.