ABSTRACT Purpose: To explore the role and mechanisms of octreotide in neurofunctional recovery in the traumatic brain injury (TBI) model. Methods: Rats were subjected to midline incision followed by TBI in the prefrontal cortex region. After 72 hours, the behavioural and neurological deficits tests were performed, which included memory testing on Morris water maze for 5 days. Octreotide (15 and 30 mg/kg i.p.) was administered 30 minutes before subjecting to TBI, and its administration was continued for three days. Results: In TBI-subjected rats, administration of octreotide restored on day 4 escape latency time (ELT) and increased the time spent in the target quadrant (TSTQ) on day 5, suggesting the improvement in learning and memory. It also increased the expression of H2S, Nrf2, and cystathionine-γ-lyase (CSE) in the prefrontal cortex, without any significant effect on cystathionine-β-synthase. Octreotide also decreased the TNF-α levels and neurological severity score. However, co-administration of CSE inhibitor (D,L-propargylglycine) abolished octreotide-mediated neurofunctional recovery, decreased the levels of H2S and Nrf2 and increased the levels of TNF-α. Conclusions: Octreotide improved the neurological functions in TBI-subjected rats, which may be due to up-regulation of H2S biosynthetic enzyme (CSE), levels of H2S and Nrf2 and down-regulation of neuroinflammation.