Depression is a common psychological disease, and nerve injury is the key link of depression. The molecular mechanism involved in this link needs to be explored. miR-542-3p can reduce the degree of hippocampal neuronal damage in rats, but its mechanism in the neural damage of depression is still unclear. HT-22 cell injury was induced by corticosterone (CORT). After overexpression or knockdown of miR-542-3p, CORT-induced HT-22 cell injury was tested by cell counting kit-8 (CCK-8) assay, lactate dehydrogenase (LDH) assay and flow cytometry. Inflammatory and oxidative stress indicator levels were analyzed by kit and flow cytometry. The target genes of miR-542-3p were obtained by database analysis, and the targeting relationship between miR-542-3p and phosphatase and tensin homolog (PTEN) was explored based on dual luciferase assay. After PTEN overexpression or application of AKT pathway agonist MK-2206, the degree of cell damage, inflammation, and oxidative stress were detected again. CORT was used to induce depression in mice. Pathological changes of brain tissue structure and neuronal survival were observed by pathological staining. The miR-542-3p, PTEN, and AKT/GSK3β/β-catenin pathway protein levels in vivo and in vitro were detected by qRT-PCR and Western blot. Overexpression/knockdown of miR-542-3p alleviated/aggravated CORT-induced cell injury, inflammation, and oxidation levels in HT-22 cells (P < 0.05). Meanwhile, overexpressed miR-542-3p can reduce neurological damage of mice. miR-542-3p can target PTEN, and it can trigger the AKT/GSK3β/β-catenin pathway by targeting PTEN expression to reduce CORT-induced nerve injury (P < 0.05). miR-542-3p can reduce CORT-induced hippocampal neuronal damage by targeting PTEN and activating the AKT/GSK3β/β-catenin pathway.