Glycogen synthase kinase 3 (GSK-3) is a constitutively active kinase that has been implicated in the mechanism of action of mood stabilizers. According to the neurogenic hypothesis of depression, newborn neurons in the adult dentate gyrus are required for the antidepressant effects of certain agents. We demonstrate that administration of the GSK-3 inhibitor VP2.51 (2.5 mg/kg ip, for 3.5 weeks) increases cell proliferation (pH3+ cells), as well as the short- and long-term survival of newborn neurons (assessed by the 24 h survival of BrdU+ and DCX+ neurons), while significantly increasing the commitment of cells to the granule neuron lineage (Prox1 immunoreactivity). In parallel, VP2.51 induces a net antidepressant effect, as judged by the decrease in the immobility time in the forced swim test of naïve mice (non-stressed mice), as well as a therapeutic effect on previously stressed mice (Porsolt-induced stress). Interestingly, the morphological changes were found prominently in the ventral region of the hippocampus. We found that these effects are neurogenesis dependent by combining the antimitotic temozolomide (50 mg/kg ip) with the drug. Importantly VP2.51 did not provoke changes in weight or in a battery of behavioral tests (learning/memory and activity tests). As the effects of VP2.51 were concomitant with the increase in β-catenin expression and a shift towards the inactive form of GSK-3, we suggest that VP2.51 has therapeutic benefits following stress, and it may be a preventive treatment in situations where a potential depressive state and/or loss of memory is associated with diminished neurogenesis, through selective GSK3-beta inhibition.