Although depression is highly comorbid with substance use disorders, little is known about the clinical course and outcomes of methamphetamine (MA) users with depressive symptoms and syndromes. In this study of MA-dependent individuals entering psychosocial treatment, we predicted that (1) depressive symptoms would decline during treatment, an effect that would vary as a function of MA use and (2) depression diagnoses post-treatment would be associated with poorer outcomes. Participants (N = 526) were assessed for depression, substance use, and psychosocial outcomes at baseline, treatment discharge, and 3-year follow-up. Depressive symptoms declined significantly during treatment, an effect that was greatest among those who abstained from MA. Major depression at follow-up was associated with poorer MA use outcomes and impairment across multiple domains of functioning. The findings highlight the relationship of depressive symptoms and diagnoses to treatment outcomes, and suggest a need for further studies of depression in populations using MA.