Abstract Background Perinatal depression is of substantial public health importance in low and middle income countries. The study aimed to evaluate the impact of a mental health intervention delivered by non-specialist health workers on symptom severity and disability in women with perinatal depression in Uganda. Methods Pregnant women in the second and third trimester were consecutively screened using the Luganda version of the 9-item Patient Health Questionnaire (PHQ-9). Women who scored ≥5 on the PHQ-9 and who were confirmed to have depression by a midwife were recruited into a treatment cohort and offered a psychological intervention in a stepped care fashion. Women were assessed with PHQ-9 and WHODAS-2.0 at baseline and again at 3 and 6 months after the intervention. Negative regression analysis was done to examine change in PHQ-9 and WHODAS-2.0 scores from baseline to end line. Data were analysed using STATA version 14. Results A total of 2652 pregnant women (98.3%) consented to participate in the study and 153 (5.8%) were diagnosed as depressed. Over a quarter (28.8%) reported having experienced physical interpersonal violence (IPV) while (25.5%) reported sexual IPV in the past year. A third (34.7%) of women diagnosed with depression received 4 or more group PST sessions. There was a mean reduction in PHQ-9 score of 5.13 (95%CI − 6.79 to − 3.47, p < 0.001) and 7.13 (95%CI − 8.68 to − 5.59, p < 0.001) at midline and endline, respectively. WHODAS scores reduced significantly by − 11.78 points (CI 17.64 to − 5.92, p < 0.001) at midline and − 22.92 points (CI 17.64 to − 5.92, p < 0.001) at endline. Clinical response was noted among 69.1% (95%CI 60.4–76.6%) and 93.7% (95%CI 87.8–96.8%) of respondents at midline and endline, respectively. Conclusion An evidence based psychological intervention implemented in primary antenatal care by trained and supervised midwives in a real-world setting may lead to improved outcomes for women with perinatal depression. Future randomised studies are needed to confirm the efficacy of this intervention and possibility for scale up.