Currently, hormonal therapy for endometriosis faces challenges in achieving a balance between treatment and preserving the chance of pregnancy. Therefore, the development of non-hormonal therapy holds significant clinical importance. Angiogenesis is a hallmark of endometriosis, and anti-angiogenic therapies targeting the hypoxia-inducible factor-1α (HIF-1α) pathway are considered potential approaches for endometriosis. However, angiogenesis is also involved in numerous physiological processes, including pregnancy, and systemic anti-angiogenesis may lead to severe adverse effects. To address this, a cRGD-modified liposome nanodrug (cRGD-LP-ART) is synthesized, which enhances drug efficacy while reducing adverse reactions. Artesunate (ART), a non-hormonal drug used to treat malaria, has shown anti-angiogenic effects beyond its original indications in various benign and malignant diseases. With cRGD modification, cRGD-LP-ART can target ectopic lesions and inhibit local angiogenesis by suppressing the HIF-1α/vascular endothelial growth factor (VEGF) pathway. Furthermore, cRGD-LP-ART exhibits better therapeutic effects than free ART, without affecting ovarian function or causing atrophy of the eutopic endometrium, making it a promising new option for non-hormonal therapy of endometriosis. As a combination of liposomes and a clinically approved drug, cRGD-LP-ART holds great potential and clinical prospects for the treatment of endometriosis.