Background Postpartum depression (PPD) is a significant cause of maternal morbidity and has severe consequences on the well-being of mothers, new-borns, families, and communities. PPD reduces the mother’s response to the child’s needs. In severe cases, mothers suffering from PPD are prone to postpartum psychosis, commit suicide and, in rare cases, infanticide. We aimed to determine the prevalence and understand the factors associated with PPD among mothers in southwestern Uganda.

Methods This was a cross-sectional study between November 2019 and June 2020 among 292 mothers, six to eight weeks’ postpartum. Mothers were selected from three health facilities in southwestern Uganda and enrolled using stratified consecutive sampling. Postpartum depression was clinically diagnosed using the Diagnostic and Statistical Manual of Mental Disorders V. The factors associated with PPD were assessed by using a structured interviewer administered questionnaire. The factors were analyzed using bivariate chi square analyses and multivariate logistic regression.

Results Overall prevalence of PPD was 27.1% (95% CI: 22.2–32.5). This did not vary by the number of previous births or mode of birth. Five factors associated with PPD were low perceived social support, HIV positive status, rural residence, obstetrical complications and the baby crying excessively.

Conclusion Prevalence of PPD in Mbarara and Rwampara districts is higher than what has previously been reported in Uganda indicating an urgent need to identify pregnant women who are at increased risk of PPD to mitigate their risk or implement therapies to manage the condition.