Endometriosis is a chronic inflammatory gynecological condition marked by the presence of tissue similar to the endometrium grows outside the uterus, often leading pelvic pain and infertility. This study explores how enhancer of zeste homolog 2 (EZH2) influences endometriosis, particularly through its interaction with estrogen receptors (ERs). We found that EZH2 reduces ER alpha expression, allowing ER beta to bind to the tumor necrosis factor alpha (TNF alpha) promoter and increase TNF alpha levels, fueling inflammation. In mice, the EZH2 inhibitor GSK343 reduced TNF alpha levels and endometriosis progression, similar to gene knockdown of ER beta or EZH2. In human samples, endometriotic tissue showed higher levels of EZH2 and ER beta and lower levels of ER alpha than in controls. Thus, EZH2 promotes TNF alpha-driven inflammation, contributing to endometriosis. Targeting EZH2, as with GSK343, could be a promising therapeutic strategy for endometriosis treatment.