An herbal medicinal product consisting of three kinds of herbal materials, Prunella vulgaris L. (Lamiaceae), Clematis chinensis Osbeck (Ranunculaceae) and Trichosanthes kirilowii Max. (Cucurbitaceae) has been prescribed in the clinic for treating rheumatoid arthritis in Korea. In the present study, we investigated the antidepressive effect of this herbal complex extract (HCE) on lipopolysaccharide (LPS)-induced depression-like behavior. The effects of HCE on LPSinduced depressive-like behaviors were evaluated using a forced swimming test (FST) and splash test. In addition, we also evaluated locomotor activity and anxiety-like behaviors using the open field test and elevated plus-maze (EPM) test.Inflammatory cytokines were evaluated in the cortical regions. HCE attenuated anxiety-like behavior in the EPM test and depressive- and anhedonia-like behaviors induced by LPS in the FST and splash test. In addition, LPS-induced increases in the phosphorylation levels of protein kinase B (Akt) and glycogen synthase kinase 3 beta (GSK-3β) and expression levels of proinflammatory factors in the cortex were normalized by HCE. Moreover, decreases in the level of BDNF in the cortex were attenuated by HCE. These results suggest that HCE attenuates inflammation-induced depression-like behaviors through its normalization of Akt-GSK-3β signaling and proinflammatory factors and its upregulation of BDNF in the cortex and that HCE has therapeutic potential for depressive disorders in inflammatory states.