In this study, we investigated the antidepressant-like effects of the hexane (HCP), ethyl acetate (ECP) and methanol (MCP) extracts of the roots of Casimiroa pubescens Ramírez (Rutaceae) using the forced swim test (FST). In an initial experiment, each extract was orally administered to mice only once 60 min before to the FST. In a second experiment, doses were administered 24, 7 and 1 h before testing. Our results showed that the triple administration of the extracts provided a stronger effect than single administration. However, the combination of HCP at 7.5 mg/kg and imipramine (IMI) at 12.5 mg/kg showed the greatest effect. The coumarins 3-(1',1', dimethyl allyl)-herniarin, auraptene, 8-geranyl-oxy psoralen, isopimpinellin and the flavonoid zapotin were isolated from the extracts. The hexane extract of C. pubescens showed an antidepressant-like activity, which may inspire further studies on developing new antidepressant agents.