Resolvin D1 (RvD1) and D2 (RvD2) are lipid mediators that are derived from docosahexaenoic acid. We recently demonstrated that intracerebroventricular (i.c.v.) infusions of RvD1 or RvD2 attenuate lipopolysaccharide-induced depression-like behaviors via mammalian target of rapamycin complex 1 signaling. However, the antidepressant effects of RvD1 and RvD2 have not been fully investigated. Here, we examined the antidepressant effects of RvD1 and RvD2 using the tail suspension test (TST) and forced swim test (FST) in murine chronic unpredictable stress (CUS) model. Male BALB/c mice (7 weeks) were subjected to 5 weeks of CUS and then received with a single i.c.v. infusion of RvD1 (10 ng), RvD2 (10 ng), or vehicle. In vehicle-infused mice, CUS significantly increased immobility in the TST both 2 and 24 h after i.c.v. infusion, these depression-like behaviors were significantly ameliorated by RvD1 or RvD2. Similar results were obtained from the FST. Intracerebroventricular infusion of RvD1 or RvD2 did not affect locomotor activity. These results demonstrate that RvD1 and RvD2 produce rapid and sustained antidepressant effects in the CUS model.