AIM: To observe the effect of dexmedetomidine (DEX) on cerebral ischemia and reperfusion (I/R) injury and investigate the possible mechanism of nuclear factor erythroid derived 2-like 2 (Nrf2) mediated ferroptosis on hippocampal neurons. METHODS: The oxygen glucose deprivation/reoxygenation (OGD/R) model in rat primary cultured hippocampal neurons was simulated, DEX (50 μmol/L) and Nrf inhibitor BRU (100 nmol/L) were used to observe the changes of ROS levels by DHE fluorescence probe. The middle cerebral artery occlusion model in male SD rats were established, the degree of neurological impairment was detected by Longa score, and cerebral infarct size was detected by TTC staining. The Fe2+ concentration and levels of oxidative stress related factors were detected, oxidative stress and ferroptosis related protein expressions were detected by Western blot. RESULTS: The fluorescence intensity of DHE in OGD/R+Dex Group was lower than that in CON group, and the fluorescence intensity of DHE in OGD/R+DEX + BRU group was higher than that in OGD/R+Dex group. Compared with Sham group, the Longa score and cerebral infarct size in I/R group were significantly increased (P<0.01), the levels of SOD, CAT, GSH and GSH-PX were significantly decreased. MDA and Fe2+ concentrations were increased, the protein expressions of Nrf2, HO-1, GPX4, FTH1 and FPN1 were decreased, and TFR1 protein expression was increased. Compared with I/R group, in DEX+I/R group, the Longa score and cerebral infarct size were decreased (P<0.01), the levels of SOD, CAT, GSH and GSH-PX were increased. MDA and Fe2+ concentrations were decreased, the protein expressions of Nrf2, HO-1, GPX4, FTH1 and FPN1 were increased, and TFR1 protein expression was decreased. The Nrf2 inhibitor Bru reversed the role of DEX. CONCLUSION: DEX protects against cerebral I/R injury through activating Nrf2 signaling pathway and inhibiting ferroptosis in hippocampal neurons.