Depression is a widespread, withering illness, resulting in a massive personal suffering and economic loss. The chronic exposure to stress may be involved in the etiology of human psychiatric disorders; such as depression. In the current study, the animals were subjected to chronic unpredictable mild stress (CUMS) for 14 days. Saxagliptin (SAXA) is a member of dipeptidyl peptidase-4 (DPP-4) inhibitors class. The current study was the first one to examine the anti-depressive effect of SAXA in an experimental model of CUMS-induced depression in rats and the possible underlying mechanisms. Animals were orally treated with SAXA (0.5, 1 and 2 mg/kg) for 14 days. SAXA treatment reversed the CUMS-induced alterations in the behavioral, biochemical as well as histopathological parameters. Moreover, it hindered the CUMS-induced increase in the oxidative stress, inflammatory, and apoptotic markers. On the other hand, it increased the monoamines levels and the neurogenic brain derived neurotrophic factor (BDNF). In addition, SAXA treatment increased the incretin hormones, glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), which are linked to the activation of protein kinase B (AKT)/phosphatidylinositol3-kinase (PI3K) pathway. In conclusion, the current study revealed that the modulation of the interplay between the key events involved in depression, including oxidative stress, inflammation, and GLP-1/PI3K/AKT signaling pathway, can explain the anti-depressant activity of SAXA.