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Inhibition of glycogen synthase kinase-3 (GSK-3) by pharmacological tools can produce antidepressant-like effects in rodents. However, the GSK-3 isoform(s) and brain region(s) involved in regulating these behavioral effects remain elusive. We studied the effects of bilateral intra-hippocampal injections of lentivirus-expressing shRNA targeting GSK-3β on behavioral performance in mice subjected to chronic stress. Pre-injection of lentivirus-expressing GSK-3β shRNA into the hippocampal dentate gyrus significantly decreased immobility time in both forced swim and tail suspension tests, while the locomotor activity of these mice was unchanged. These results suggest that lentiviral GSK-3β shRNA injection induces antidepressant-like effects in chronically stressed mice. Under these conditions, the expression levels of GSK-3β were persistently and markedly reduced in the hippocampus following GSK-3β shRNA injection. To our knowledge, this is the first demonstration that a single injection of lentivirus-expressing GSK-3β shRNA in the hippocampal dentate gyrus of chronically stressed mice has antidepressant-like effects elicited by gene silencing.