Objective: This study aimed to investigate the neuroprotective effects and mechanisms of exogenous H?S (using sodium hydrosulfide [NaHS] as a donor) in a rat model of middle cerebral artery occlusion (MCAO). Methods: Sixty Sprague-Dawley (SD) rats were randomly divided into a sham operation group, an I/R model group, and an I/R+NaHS treatment group. The sham group underwent the same procedures as the model group except for middle cerebral artery occlusion. The treatment group received an intraperitoneal injection of 6.4 mg/kg NaHS. Cerebral infarct volume was detected by TTC staining. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) content were measured by ELISA. Nrf2 mRNA expression was detected by qRT-PCR, and the phosphorylation level of Nrf2 protein was analyzed by Western blot. Results: Compared with the sham group, the I/R model group showed significantly increased neurological deficit scores and cerebral infarct volume, abnormal elevation of SOD activity and MDA content, and significantly upregulated Nrf2 mRNA expression and p-Nrf2/Nrf2 protein ratio in the peri-ischemic area. Compared with the I/R model group, the NaHS treatment group exhibited significantly decreased neurological deficit scores and infarct volume, enhanced SOD activity, reduced MDA content, more significantly increased Nrf2 mRNA expression and total protein level, and a decreased p-Nrf2/Nrf2 ratio. Conclusion: Exogenous H?S inhibits excessive activation of oxidative stress in cerebral I/R injury, reduces cerebral infarct volume, and exerts neuroprotective effects. This effect may be related to the inhibition of partial MAPK pathway phosphorylation and promotion of Nrf2 nuclear translocation and transcriptional activity, providing a theoretical basis for the clinical application of H?S in ischemic stroke intervention.