Patients with inflammatory bowel disease (IBD) have higher rates of psychiatric pathology including depression. The dextran sulfate sodium (DSS)-treated mouse is a well-characterized animal model of colitis that exhibits both IBD- and depressive-like symptoms. Recently, we found that DSS-treated mice decreased phosphorylation of AMP-activated protein kinase (AMPK) in the hippocampus and rectum. AMPK is known to be associated with the regulation of inflammation, autophagy, and neurogenesis. Hence, we examined whether AMPK activator resveratrol (RSV) prevents the DSS-induced colitis and depressive-like behavior in mice. DSS-treated mice exhibited the colitis-like symptoms, and depressive-like behavior in the tail-suspension test. Moreover, DSS-treated mice showed the hippocampal and rectal decrease in p-AMPK and LC3Ⅱ/Ⅰ levels as well as increase in p-p70S6K (a downstream target of mTORC1), p62, pro-inflammatory cytokines and cleaved caspase-3 levels, and the reduction of cell proliferation in the dentate gyrus of hippocampus. Treatment with RSV prevented these abnormalities in DSS-treated mice, and induced LC3-positive puncta in the hippocampus. These findings indicate that activation of AMPK in the hippocampus-gut may be involved in the antidepressant and anti-inflammatory effects of RSV in DSS-treated mice.