The PP2C family member Wild-type p53-induced phosphatase 1 (Wip1) critically regulates DNA damage response (DDR) under stressful situations. In the present study, we investigated whether Wip1 expression was involved in the regulation of DDR-induced and depression-related cellular senescence in mouse hippocampus. We found that Wip1 gene knockout (KO) mice showed aberrant elevation of hippocampal cellular senescence and of gamma-H2AX activity, which is known as a biomarker of DDR and cellular senescence, indicating that the lack of Wip1-mediated gamma-H2AX dephosphorylation facilitates cellular senescence in hippocampus. Administration of the antidepressant fluoxetine had no significant effects on the increased depression-like behaviors, enriched cellular senescence, and aberrantly upregulated hippocampal gamma-H2AX activity in Wip1 KO mice. After wildtype C57BL/6 mice were exposed to the procedure of chronic unpredictable mild stress (CUMS), cellular senescence and gamma-H2AX activity in hippocampus were also elevated, accompanied by the suppression of Wip1 expression in hippocampus when compared to the control group without CUMS experience. These CUMS-induced symptoms were effectively prevented following fluoxetine administration in wildtype C57BL/6 mice, with the normalization of depression-like behaviors. Our data demonstrate that Wip1-mediated gamma-H2AX dephosphorylation may play an important role in the occurrence of depression-related cellular senescence.