Clinical and preclinical studies have shown that the NMDA receptor antagonist ketamine exerts rapid and long-lasting antidepressant effects. Although ketamine metabolites might also have potential antidepressant properties, controversial results have been reported on (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) in particular and there is little information on the effects of other ketamine metabolites. Here we aimed to compare the effects of (R)-norketamine ((R)-NK), (S)-NK, (2R,6R)-HNK and (2S,6S)-HNK in a mouse model of depression induced by chronic corticosterone (CORT) injection. None of these ketamine metabolites at doses up to 20 mg/kg showed antidepressant-like activity in naïve male C57BL6/J mice. Chronic CORT treatment increased immobility in the forced swim test and caused anhedonic-like behaviors in the female encounter test. A single administration of (R)-ketamine, but not an SSRI fluoxetine, showed antidepressant-like activity in chronic CORT-treated mice. (S)-NK and (2S,6S)-HNK dose-dependently reduced the increased immobility at 30 min after injection, while (R)-NK or (2R,6R)-HNK did not. Additionally, (S)-NK and (2S,6S)-HNK improved anhedonic-like behaviors at 24 h after injection. These results suggest that (S)-ketamine metabolites (S)-NK and (2S,6S)-HNK have potent acute and sustained antidepressant effects.