Background <p>G protein-coupled estrogen receptor 1 (Gper1) is widely expressed in the brain, while its function in traumatic brain injury (TBI) remains poorly understood. This study aims to investigate the role of Gper1 in TBI pathology and the underlying mechanisms using a mouse model.</p> Methods <p>Gper1 knockout (<i>Gper1</i>^<i>KO</i>) mice were generated, and TBI was induced via controlled cortical impact (CCI). Brain water content, cell apoptosis, and neuroinflammation were assessed using real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and TUNEL staining. Behavioral outcomes, including cognitive and anxiety-related behaviors, were evaluated using the open field test and Y-maze test.</p> Results <p>Gper1 expression was significantly upregulated in the brain tissues of TBI mice. Knockout of <i>Gper1</i> led to exacerbated TBI-induced outcomes, including increased brain edema, blood-brain barrier disruption, and aggravated cell apoptosis and neuroinflammation in the cortex. Behaviorally, <i>Gper1</i>^<i>KO</i> mice displayed more severe cognitive impairments and anxiety-like behaviors compared to wild-type mice.</p> Conclusions <p>Gper1 inhibition exacerbates TBI-induced neurological and behavioral impairments, which suggests that Gper1 may be a potential therapeutic target for mitigating TBI-associated brain injury.</p>