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Renal ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury and is associated with mitochondrial dysfunction, excessive reactive oxygen species (ROS) production, and tubular cell apoptosis. Sigma-1 receptor (Sigma1R), an intracellular chaperone, helps maintain mitochondrial homeostasis and cell survival. Here, Sigma1R expression was significantly downregulated in renal IRI. Fluvoxamine treatment ameliorated renal dysfunction and reduced apoptosis in vivo, whereas Sigma1R overexpression preserved mitochondrial membrane potential and attenuated ROS accumulation in HK-2 cells subjected to hypoxia/reoxygenation. The findings support the functional involvement of Rac1 in Sigma1R-mediated enhancement of PINK1/Parkin-mediated mitophagy, which may facilitate the clearance of damaged mitochondria and restore mitochondrial quality control. Overall, Rac1 is involved in Sigma1R-mediated mitophagy and mitochondrial protection, highlighting Sigma1R as a potential therapeutic target for renal IRI.