Background: Postpartum depression explains various groups of depressive symptoms and syndromes that take place during the first 6 weeks following birth. The postpartum period is a critical time where both mild and severe mood disorders occur. The familiar forms are baby blues and postpartum depression. Determination of the prevalence and associated factors of postpartum depression is mandatory for early detection and treatment. Methods: Institution based cross-sectional study was conducted from May to June 2018 by using systematic random sampling technique. The data was collected from each health centers and referral hospital. The study participants were eligible women who came to Debre Berhan referral hospital and health centers for postnatal care and vaccination service. The Edinburg postnatal depression scale was used to assess postpartum depression. The collected data were coded and entered into Epi-info version 7 and transported to SPSS version 20 for analysis. Both Bivariate and Multivariate Binary Logistic Regression were done to identify associated factors. During bivariate analysis, variables with p-value < 0.05 were included in multivariate analysis. Odds Ratios and their 95% Confidence Intervals were computed and variables with p-value less than 0.05 were considered significantly associated factors (multivariate analysis). Results: A total of 308 mothers who attend postnatal care included with a response rate of 100%. The prevalence of postnatal depression was found to be 15.6 %( 95%CI=11.7, 19.8). Being widowed/widower (AOR=4.17 (95% CI=1.14, 15.20)), having poor social support (AOR=5.11(95% CI= 1.00, 26.18), having hospitalized child (AOR=3.32(95%CI= 1.39, 7.93), and having died close family or relative (AOR=2.92(95%CI=1.01, 8.50)) were significantly associated factor with postpartum depression. Conclusions: Though significant proportions of mothers are depressed, the prevalence of postpartum depression was lower than most studies in different areas. It will be better if health care professionals give special attention to maternal mental health issues and consult mothers to mitigate the problem. It will be better if Health care professionals working in maternal and child health clinics to give special attention to mothers who are widowed/widower, having poor social support, having hospitalized child, having died close family or relative. Therefore, the authors failed to accept both null hypotheses.