Endometriosis is an estrogen-dependent inflammatory gynecological disorder that is pathologically defined as the growth of endometrial glands and stroma outside of the uterine cavity. It is estimated that more than 15% of women of reproductive age are affected by endometriosis. Immunological and inflammatory responses, anti-apoptotic effects and angiogenesis processes have been reported to be involved in endometriosis. Surgery and pharmacotherapy are applied in the treatment of this disease. Frustratingly, a high recurrence rate and/or side effects are observed during and after the treatments. In our previous study, we designed and synthesized serial analogs of naturally occurring flavokawain chalcones. Among these molecules, FK-morph exhibited excellent anti-inflammatory activity and showed therapeutic potential in vitro and in vivo. In the current study, we demonstrate the beneficial effects of FK-morph on a surgically induced endometriosis rat model. After treatment with FK-morph, the volumes and adhesion scores of implants in rats were effectively reduced and the levels of inflammatory cytokines and related chemokines in peritoneal fluid and blood were significantly downregulated. FK-morph also mediated cell apoptosis of endometriosis foci. In addition, the angiogenesis process was attenuated by decreasing the expression of VEGF. Meanwhile, the underlying mechanism was further explored. FK-morph effectively reduced the expression of Akt, p-Akt, PI3K, p-PI3K and NF-κB in endometriosis lesions. Overall, the results revealed the efficacy of FK-morph against endometriosis by reducing the levels of inflammatory factors, accelerating apoptosis and attenuating angiogenesis, which may be associated with blocking the activation of the PI3K/Akt and NF-κB signaling pathways.