Objective To investigate the effect of the G protein-coupled estrogen receptor (GPER) on oxidative stress and its possible mechanisms for reducing renal ischemia reperfusion injury. Methods Female ovariectomized rats were divided into the ovariectomy (OVX), renal ischemia reperfusion (OVX+I/ R), estrogen intervention (OVX+I/ R+E₂ ), GPER-specific agonist (G1) intervention (OVX+I/ R+G1), and estrogen+GPER specific blocker G15 intervention (OVX+I/ R+G15+ E₂ ) groups ( n= 8 rats per group). Serum creatinine ( Cr) and urea nitrogen ( BUN) levels were measured, and histopathological examination using hematoxylin and eosin ( HE) staining was used to observe the pathological morphology of the renal tissues. Superoxide dismutase and malondialdehyde activities were detected, and Western blot was used to observe p-PI3K and p-Akt expressions in the renal tissues of each group. Results Compared with the OVX group, serum Cr and BUN levels were increased, pathological damage to the renal tissue was significant, oxidative stress was aggravated, and p-PI3K and p-Akt protein expression levels were significantly decreased in the OVX+I/ R group (allP< 0. 01). Compared with the OVX + I/ R group, the serum Cr and BUN levels were decreased, renal tissue pathological damage was reduced, oxidative stress was reduced, p-PI3K and p-Akt protein expressions were increased (all P< 0. 01), and the GPER-specific inhibitor, G15, partially eliminated the protective effect of E₂ on renal ischemia reperfusion injury in the E₂ and G1 intervention groups. Conclusions During renal ischemia reperfusion injury, E₂ and G1 may reduce oxidative stress to alleviate the injury. GPER may mediate the protective effect of E₂ , and its mechanism may involve activating the PI3K/ Akt signaling pathway.