Background: Low-birth weight (LBW) (<2500 g) is considered to be a leading cause of cognitive impairment and physical disabilities in children. Incidence of LBW in South Asia has been reported to be as high as 33%. We investigated the association between antenatal depression and LBW in an urban community, in Karachi, Pakistan. Methods: A total of 1357 pregnant women in their third trimester were recruited into the study. They were screened for antenatal depression with Edinburgh postnatal depression scale. Self-reporting questionnaire was also used to measure psychological distress. Birth weights of 763 newborns were obtained from the hospital records. Results: We did not find a significant association between antenatal depression and LBW (odds ratio 0.881, 95%CI 0.732-1.060) in mothers attending a charity run hospital in an urban setting in Pakistan. Conclusion: Antenatal depression is not associated with LBW in this urban population in Pakistan. However, the prevalence of depression is high during pregnancy. There is a need to develop culturally adapted psychosocial interventions to address the high rates of depression for this population group.