Anxiety experienced by women during pregnancy is highly prevalent, especially in resource-poor settings and strongly predicts postnatal common mental disorders (CMDs), anxiety and depression. We evaluated the effectiveness of an anxiety-focused early prenatal intervention on preventing postnatal CMDs. This study was a phase 3, two-arm, single-blind, randomized controlled trial conducted in Pakistan with women who were ≤22 weeks pregnant and had at least mild anxiety without clinical depression. Participants were randomized to the Happy Mother-Healthy Baby program, based on cognitive behavioral therapy, consisting of six one-on-one intervention sessions in pregnancy delivered by non-specialist providers, or to enhanced care alone. The primary outcome was major depression, generalized anxiety disorder or both at 6 weeks after delivery. Overall, 755 women completed postnatal assessments (380 (50.3%), intervention arm; 375 (49.7%) enhanced-care arm). The primary outcomes were met. Examined jointly, we found 81% reduced odds of having either a major depressive episode (MDE) or moderate-to-severe anxiety for women randomized to the intervention (adjusted odds ratio (aOR) = 0.19, 95% CI 0.14-0.28). Overall, 12% of women in the intervention group developed MDE at 6 weeks postpartum, versus 41% in the control group. We found reductions of 81% and 74% in the odds of postnatal MDE (aOR = 0.19, 95% CI 0.13-0.28) and of moderate-to-severe anxiety (aOR = 0.26, 95% CI 0.17-0.40), respectively. The Happy Mother-Healthy Baby program early prenatal intervention focusing on anxiety symptoms reduced postpartum CMDs. ClinicalTrials.gov identifier NCT03880032 .