Endometriosis causes severe chronic pelvic pain and infertility. Because the standard medication and surgical treatments of endometriosis show high recurrence of symptoms, it is necessary to improve the current treatment options. In the initial study, we examined whether niclosamide can be a useful drug for treating endometriosis in a preclinical setting. Endometriotic implants were induced using an established mouse model involving transimplantation of mouse endometrial fragments to the peritoneal wall of recipient mice. When the recipient mice were treated with niclosamide for 3 wk, niclosamide reduced the size of endometriotic implants with inhibition of cell proliferation and inflammatory signaling, including RELA (NFKB) and STAT3 activation, but did not alter expression of steroid hormone receptors. To identify genes whose expression is regulated by niclosamide in endometriotic implants, RNA-sequencing was performed, and several genes downregulated by niclosamide were related to inflammatory responses, WNT, and MAPK signaling. In a second study designed to assess whether niclosamide affects reproductive function, the recipient mice started receiving niclosamide after the induction of endometriosis. Then, the recipient mice were mated with wild-type males, and treatments continued until the pups were born. Niclosamide-treated recipient mice became pregnant and produced normal size and number of pups. These results suggest that niclosamide could be an effective therapeutic drug and acts as an inhibitor of inflammatory signaling without disrupting normal reproductive function.