The benefits of creatine supplementation have been reported in a broad range of central nervous system diseases, including depression, although the mechanisms underlying these effects remain to be understood. In the present study, we investigated the ability of creatine to counteract the morphological and behavioral effects elicited by chronic administration of corticosterone (CORT, 20 mg/kg, p.o.) for 21 days to mice, a pharmacological model of depression that mimics exposure to stress. CORT treatment increased immobility time in the tail suspension test (TST) and forced swim test (FST), as well as latency to immobility in the FST, and decreased the sucrose consumption in the sucrose preference test (SPT). These behavioral effects were associated with decreased hippocampal cell proliferation and neuronal differentiation and increased glial fibrillary acid protein (GFAP) immunostaining (suggestive of astrogliosis) in dentate gyrus (DG) of the hippocampus. These CORT-induced alterations were abolished by treatment with either fluoxetine (a conventional antidepressant) or creatine for 21 days (both 10 mg/kg, p.o.). In addition, fluoxetine, but not creatine, was able to reverse the CORT-induced reduction in serum CORT levels. Collectively, our results suggest that creatine produces morphological alterations that contribute to the improvement of depressive-like behaviors triggered by chronic CORT administration in mice.