Abstract: Objective To investigate the protective effect and mechanism of sigma-1 receptors on corticosterone-induced mitochondrial damage in astrocytes. Methods A corticosterone-induced primary astrocyte damage model was established, and the sigma-1 receptor-specific agonist PRE-084 was used for intervention. Mitochondrial membrane potential, ATP production, and the expression of mitochondrial dynamics-related proteins were assessed. Furthermore, the mitochondrial fission inhibitor mdivi-1 was given to observe its effect on the protective role of sigma-1 receptors. Results Corticosterone-induced damage to astrocytes resulted in decreases in mitochondrial membrane potential and ATP production. The expression of mitochondrial fusion proteins optic atrophy 1 (OPA-1) and mitochondrial fusion protein 1 (Mfn1) showed no significant changes, but the phosphorylation of the mitochondrial fission protein dynamin-related protein 1 (Drp-1) was significantly reduced. Activation of sigma-1 receptors reversed these damages, showing a protective effect. After treatment with mdivi-1, the protective effect of sigma-1 receptor activation was abolished. Conclusions Activation of sigma-1 receptors can protect astrocyte mitochondria from corticosterone-induced damage, which may be related to promoting mitochondrial fission.