Endometriosis is a chronic inflammatory condition in women, and obesity leads to an inflammatory condition that is directly involved in the etiology of endometriosis. However, observational studies have shown an inverse correlation between endometriosis and a low body mass index (BMI). Obesity does not protect against endometriosis, and on the contrary, an increased BMI may lead to more severe forms of the disease. To determine the effect of obesity on endometriosis, diet-induced and genetically engineered obese mouse models were integrated with endometriosis mouse models with fluorescence-tagged ectopic lesions. High-fat diet-induced obese mice revealed a significant increase in endometriosis development compared with regular-diet control mice. However, obese recipient mice with leptin deficiency and leptin receptor deficiency showed suppressed endometriosis development compared with control mice. Furthermore, donor uterine tissues with leptin deficiency and leptin receptor deficiency suppressed endometriosis development compared with control donor in control recipient mice. Importantly, we revealed that aberrant high levels of leptin concentration significantly increased endometriosis development compared with vehicle treatment group in control mice with normal body weight. Our results suggest that leptin and its receptor are critical for endometriosis development.