Endometriosis is a chronic inflammatory disease characterized by the growth of endometrium-like tissues outside the uterine cavity, with an unclear pathogenesis. Analysis of single-cell sequencing data revealed the pivotal role of peritoneal macrophages in the development of endometriosis. We noted significant creatine enrichment and synthesis in peritoneal macrophages of patients with endometriosis compared to women without endometriosis. To further investigate the mechanisms of creatine in endometriosis, we performed RNA sequencing and in vitro experiments. We found that creatine reprograms M2 polarization by enhancing matrix metalloproteinases and anti-inflammatory cytokines, which are involved in angiogenesis, fibrogenesis, cell adhesion, and tissue repair. The co-culture of creatine-treated macrophages promoted migration and fibrogenesis of endometrial stromal cells, as well as angiogenesis of HUVECs in vitro. In summary, this article reveals that creatine might polarize M2 macrophages, promoting the initiation, fibrosis, and angiogenesis of ectopic endometrial lesions, ultimately resulting in the development of endometriosis. These findings underscore the crucial immunomodulatory role of creatine in the pathogenesis of endometriosis, offering a promising target for therapeutic intervention.