(RS)-ketamine exerts rapid and robust antidepressant efficacy in patients, believed to be mediated by glutaminergic NMDA receptor antagonism. However, its potential for widespread clinical use is limited by its abuse liability and potential side effects. Here, Zanos et al. report that metabolism of (RS)-ketamine to (2R,6R)-hydroxynorketamine (HNK) is necessary and sufficient to exert antidepressant actions in mice. These antidepressant effects are NMDA receptor-independent but involve early and sustained activation of AMPA receptors. Importantly, (2R,6R)-HNK was not associated with ketamine-related side effects in mice.