PURPOSE: One of the important causes of morbidity and mortality in the world is traumatic brain injury (TBI), which is a process that triggers damaging mechanisms such as inflammation, oxidative stress, and apoptosis. The results of current pharmaceutical methods are not enough, and researches into new therapy modalities are needed. This study aimed to evaluate the neuroprotective effects of Urapidil (Ura), which is an alpha-1 adrenergic receptor antagonist with serotonergic activity, in a TBI model and investigating signaling pathways like high mobility group box 1 (HMGB1), BCL2-interacting protein 3-like (BNIP3L), and hypoxia-inducible factor-1 alpha (HIF1α). METHODS: Thirty-two rats were divided into four groups: control, TBI, TBI + Ura(0.5) (0.5 mg/kg), TBI + Ura(5) (5 mg/kg) groups. Tissue integrity and expressions of tumor necrosis factor-alpha (TNF-α), caspase-3 (Cas-3), tyrosine hydroxylase (TH), HIF1α, BNIP3L, and HMGB1 were assessed. Ura's biochemical oxidative stress indicators were also assessed. RESULTS: Ura treatment at both doses, significantly decreased histopathological findings, BNIP3L, HMGB1, and HIF1α expressions, TNF-α, Cas-3, TH immunexpressions, and TOS and OSI levels, and elevated TAS levels compared to TBI group. These results show that Ura regulates molecular pathways related to TBI, including neuroinflammation, mitochondrial dysfunction, and hypoxia. CONCLUSION: Ura shows promising tissue-protective effects in TBI by targeting inflammation, oxidative stress, and apoptosis. This study provides a new perspective on the need for further development of Ura for therapeutic use.