Aim:Dexmedetomidine (DEX), a selective α-2 adrenergic agonist, is known to exhibit anti-inflammatory, antioxidant, and anti-apoptotic effects after acute ischemic stroke. However, its effects after traumatic brain injury (TBI) remain an open area of interest, with limited relevant publications. This experimental study aimed to elucidate the effects of nasal (DexN) and intraperitoneal (DexP) Dex administration in an animal model and explore the underlying action mechanisms.Material and Methods:A total of 31 Wistar albino rats served as a weight-drop model to induce experimental TBI. The two treatment groups received DexN and DexP on the day of the trauma and then after 5 days. The Garcia test was performed for the neurological evaluation along with histopathological and biochemical analyses of NSE, S-100B, CASP3, GSH-PX, and TBARS.Results:The rats in the treatment group displayed better neurological outcomes, as evidenced by a higher Garcia test score (p < 0.001). Peritoneally administered Dex presented with increased anti-inflammatory and neuroprotective effects in comparison to the nasal one (p < 0.001). Nasally administered DEX demonstrated a reduction in the NSE levels (p = 0.023), indicating that it inhibited neuronal destruction. The levels of CASP3, a biochemical parameter that plays a role in apoptosis, notably declined, indicating a neuroprotective impact. Conversely, GSH-PX, which plays a role in oxidative cellular stress, exhibited a notable increase, implying an antioxidant effect. However, these results were statistically insignificant.Conclusion:The present findings support the hypothesis that a psychoactive drug, DEX, which has been conventionally used for sleep disorders and is also known for its cognitive-enhancing properties, may have beneficial effects after TBI owing to its anti-inflammatory, anti-oxidative, and neuroprotective properties.