Background <p>Traumatic brain injury (TBI) is a global health problem, and its mechanisms can be divided into primary and secondary damage. Secondary injuries play a significant role in TBI outcomes. Recent studies have shown that semaglutide, a novel glucose-dependent hypoglycemic agent, inhibits neuroinflammation and cell death in some neurodegenerative diseases. However, the association between semaglutide level and TBI remains unclear. Therefore, this study aimed to investigate the neuroprotective effects of semaglutide in patients with TBI.</p> Method <p>In total, 60 C57 male mice were randomly divided into three groups: SHAM, TBI, and SEMAGLUTIDE (operation + 50&#xa0;nmol/kg/day semaglutide). Behavioral tests, immunofluorescence, and western blotting were performed 72&#xa0;h after impact.</p> Results <p>Semaglutide reduced neuronal apoptosis, downregulated Bax expression, and increased Bcl-2 expression after TBI. Additionally, in the downstream apoptosis pathway, semaglutide regulated proteins associated with caspase-dependent and caspase-independent pathways, with the caspase-dependent pathway being the major one. Moreover, the activation of M1 microglia was also inhibited by semaglutide, which may be related to its protective effects.</p> Conclusions <p>Semaglutide inhibited apoptosis, increased neuronal survival rate, and inhibited M1 microglial activation to improve cognitive function in TBI mice. This neuroprotective effect of semaglutide may be regionally and time dependent.</p> <p><b>Trial registration number: 202204008</b></p> <p><b>Trial registrationdate: 2022Y12M3D</b></p> Graphical Abstract <p></p>