Significance: Endometriosis is an inflammatory gynecological disease of reproductive age women associated with chronic pelvic pain and infertility. Endometriosis remains as the single major cause for hysterectomy in reproductive age women in the United States. The pathogenesis of endometriosis remains an enigma in reproductive medicine. Current hormonal therapies cause undesirable side effects, reproductive health concerns, and are unable to prevent recurrence of disease. Results of the present study indicate that selective inhibition of prostaglandin E2 (PGE ₂ ) receptors EP2 and EP4 suppresses the growth and survival of endometriosis lesions, decreases pelvic pain, and restores endometrial functional receptivity through multiple mechanisms. Our novel findings provide a molecular and preclinical basis to formulate long-term nonhormonal therapy for endometriosis.