Heavy menstrual bleeding is common and debilitating but the causes remain ill defined. Rates of obesity in women are increasing and its impact on menstrual blood loss (MBL) is unknown. Therefore, we quantified BMI and MBL in women not taking hormones and with regular menstrual cycles and revealed a positive correlation. In a mouse model of simulated menstruation, diet-induced obesity also resulted in delayed endometrial repair, a surrogate marker for MBL. BrdU staining of mouse uterine tissue revealed decreased proliferation during menstruation in the luminal epithelium of mice on a high-fat diet. Menstruation is known to initiate local endometrial inflammation and endometrial hypoxia; hence, the impact of body weight on these processes was investigated. A panel of hypoxia-regulated genes (VEGF, ADM, LDHA, SLC2A1) showed consistently higher mean values in the endometrium of women with obesity and in uteri of mice with increased weight vs normal controls, although statistical significance was not reached. The inflammatory mediators, Tnf and Il6 were significantly increased in the uterus of mice on a high-fat diet, consistent with a pro-inflammatory local endometrial environment in these mice. In conclusion, obesity was associated with increased MBL in women. Mice given a high-fat diet had delayed endometrial repair at menstruation and provided a model in which to study the influence of obesity on menstrual physiology. Our results indicate that obesity results in a more pro-inflammatory local endometrial environment at menstruation, which may delay endometrial repair and increase menstrual blood loss.