Current therapies for endometriosis, which focus on reducing systemic oestrogen levels, are limited by side effects and poor efficacy. Zhao et al. previously developed two oestrogen receptor (ER) ligands with strong anti-inflammatory activity — chloroindazole (CLI) and oxabicycloheptene sulfonate (OBHS), which target ERα and ERβ, respectively. Here, they show that together, OBHS and CLI prevent the establishment of endometriotic lesions and reverse the growth and progression of established lesions in a mouse model of endometriosis, without affecting reproductive physiology and fertility.