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Objectives This study aimed to estimate the frequency of depression in mothers during the antepartum and postpartum periods and identify predictors of perinatal depression in the tertiary care hospital of Karachi, Pakistan.Design Analytical cross-sectional study.Setting Public Tertiary Care Hospital, Civil Hospital, Karachi, Sindh, Pakistan.Participants The study involved 262 mothers for the assessment of frequency and predictors of perinatal depression in Pakistan.Main outcome measures The Edinburgh Postpartum Depression Scale (EPDS) was used as the tool to screen for depression. The data were collected through a structured questionnaire encompassing the sociodemographic factors, pregnancy and birth-related information, newborn characteristics sections, family relationship and marital status and psychosocial and psychological history. Mean and SD were computed for continuous data, whereas frequencies and percentages were determined for categorical data. Pearson χ 2 test was applied to determine the association between categorical variables. Predictors of perinatal depression were identified through multivariate logistic regression.Results Out of 262 enrolled mothers, 198 screened positive for depressive symptoms using EPDS with a cut-off value ≥10. The mean age of participating mothers was 27.4±5.95 years. Approximately 39.7% of the mothers were illiterate, 75% were housewives and about 42% had a family income of less than US$126. Women with access to a healthcare facility had higher odds of antepartum depression symptoms, possibly due to poor healthcare experiences during antenatal visits. Emotional support by husband reduces the odds by 45.8% while experiencing abuse increases odds by three times. Significant predictors of postpartum depression symptoms included decision-making power, which reduced the odds of postpartum depression symptoms by 72.5% and emotional support by 80%.Conclusions The study concluded that maternal decision-making power is a significant protective factor against postpartum depression. Strikingly, access to health facilities by the mother was associated with higher odds of antepartum depression. Other factors, including household income, husband’s employment status, domestic violence, emotional support and family abuse, did not show significant associations with either antepartum or postpartum depression. These findings emphasise the importance of routine screening to identify women at risk during the perinatal period.