Depression caused by genetic and environmental factors is a kind of complicated disease. Here, we find that Gsk3β is highly expressed and phosphorylated in the brain of chronic stress mouse. Inhibition of Gsk3β lead to decreased depression like symptoms which is manifested in open field test, tail-suspension test, forced-swim test and novelty suppressed feeding test. Besides, accompanied by activated Gsk3β, we find that β-catenin is attenuated, and its target genes Cyclin D1 and c-Myc are down-regulated. Meanwhile, it was also found that Gsk3β can inhibit the Erk-Creb-BDNF signaling. These results show that Gsk3β may promote the progression of depression. Therefore, target Gsk3β may be an effective therapeutic strategy.