Research has shown that postnatal depression (PND) is higher in low- and middle-income countries as compared to higher-income countries. Despite this, little is known about practical interventions in these poorly resourced countries. This research investigated the effectiveness of a brief, prophylactic and therapeutic psychoeducational intervention in a low-resourced community in Nairobi. Two closely similar Maternal and Child Health (MCH) clinics in urban slums in Nairobi were identified and randomly selected. A total of 567 mothers formed the study population. The experimental group (284) mothers received the intervention, which included psychoeducation on PND, coping skills, healthy way of mother/child interaction and infant stimulation in addition to routine treatment, while the control group (283) mothers received treatment as usual. Data was collected using a social-demographic questionnaire and the English version of Becks Depression Inventory (BDI) at baseline. At 6 months, we reassessed both groups using BDI only. Within group comparison, the percentage reduction of depression was 35.6% among the experimental as compared to 2.3% in the control group. Between group comparison, the mean BDI depression score was significantly low in the experimental arm compared to the control arm at endline (p = 0.025). When all variables were adjusted, using a generalized linear model, BDI depression score reduction among the participants was significantly associated with the intervention (p = 0.040). A brief, psychoeducational intervention that targets the mother and her infant may reduce PND even in poorly resourced environments. Therefore, it can be integrated into existing MCH services.