Depo-Provera is an injectable contraceptive method containing medroxyprogesterone acetate. It has some adverse effects like changes in menstrual pattern, loss in bone mineral density and risk of weight gain. Therefore, this study is aimed at to investigate the effects of Depo-Provera on body weight and blood pressure among Ethiopian women. Institution based cross-sectional study design was conducted from January 2017 to April 2017. Data were analyzed using SPSS version 21 software. Paired t test, independent t-test and ANOVA were used to evaluate the presence of mean difference and relationship between changes in variables and duration of use of Depo-Provera. P-value ≤ 0.05 were considered as statistically significant.The mean weight and body mass index (BMI) of Depo-Provera users were increased significantly (p = 0.02 for mean body weight and p = 0.019, for body mass index). There was no significant difference in mean arterial blood pressure (MAP) of Depo-Provera users compared to controls or their respective pretreatment value (p-value = 0.85 for Depo-Provera users and 0.67 for non-users). The finding of this study revealed that there is an increased weight gain and BMI among Depo-Provera users compared to non-users, which really requires attention of health professionals and other stake holders.