Background: Depression and overweight are serious public health problems and the most common complications of childbearing age with many negative consequences on the mental health of women and their children in the world. Even though both have a serious impact, no study has been done in Ethiopia. Therefore, this study aimed to assess and compare the prevalence of depression and associated factors among normal and overweight reproductive-age women in Debre Berhan town. Methods: A community-based comparative cross-sectional study was conducted from April-June 2020. Patient health questionnaire-9 was used to measure the level of depression and list of threatening experience for stressful life events. Body mass index values of 18.5-24.9 and 25-29.9 kg/m 2 were used to classify as normal, and overweight, respectively. The data were entered into Epi Data V. 4.6 and were analyzed using SPSS V. 25. A statistically significant association was declared at a p-value < 0.05. Results: From 1530 participants the response rate were 96.1% and 100% for normal and overweight women, respectively. The prevalence of depression among normal weight women was 26.02% (95% CI: 23.3%, 28.73%) whereas among overweight was 32.89% (95% CI: 28.85%, 36.93%). For women who have normal weight; being exposed to stressful life events, having poor social support, and body image disturbance were statistically significant factors. For women who have overweight, stressful life events, body image disturbance, and experienced weight stigma were significantly associated. Conclusion and Recommendation: Depression among overweight women was high compared to normal weight in Debre Berhan town. Promoting social support at any aspect of health care services are very important to minimize depression. Especially for overweight women, encouraging management of medical illness, coping mechanisms for different stressful life events and potentiating self-confidence towards body image are a vital means to prevent depression. Health promotion program targeting reproductive age women with significant associated factors are important to overcome overweight and depression in Debre Berhan town.