Traumatic brain injury (TBI) triggers a series of pathophysiological events, contributing significantly to secondary injury and long-term functional deficits. While exosome therapy is beginning to emerge as a promising avenue for various injuries, its efficacy in TBI, using preclinical models that mimic the biomechanics of human acceleration/deceleration TBI, remains largely unexplored. This study investigated the capacity of human Schwann cell-derived exosomes (hSC-Exo) to improve outcomes in a model of moderate fluid percussion injury (FPI). We found that jugular infusion of hSC-Exo 30 min after trauma attenuated acute proinflammatory responses in the ipsilateral cortex and hippocampus 24 h post-TBI, as demonstrated by a reduction in levels of key inflammasome components, and decreased activation of the STAT3/pSTAT3/SOCS3 pathway. Furthermore, exosome treatment mitigated subacute histopathological changes, including a significant decrease in cerebral edema and contusion volumes at 72 h post-injury. Immunohistochemical analysis revealed a decrease in microglial activation, characterized by a shift toward a more ramified morphology. Importantly, hSC-exosome therapy led to the preservation of both sensorimotor function subacutely and cognitive performance at chronic time points. Flow cytometry analysis of peripheral blood at 21 days post-TBI demonstrated a reduction in circulating neutrophils, indicating an attenuation of chronic systemic inflammation. These findings highlight the multifaceted therapeutic benefits of hSC-Exo in a clinically-relevant FPI model, targeting both acute and chronic neuroinflammatory processes to promote functional recovery. This study provides new evidence to support hSC-exosomes as a therapeutic strategy for TBI, and emphasizes the translational potential of human exosomes for treating acute and progressive neurological injury.