Purpose <p>Endometriosis (EM) is a chronic inflammatory gynecological disorder characterized by ectopic endometrial-like lesions, where aberrant angiogenesis is a hallmark driving lesion establishment and progression. However, the transcriptional mechanisms underlying pathological vascular remodeling in EM remain unclear.</p> Methods <p>In this study, we identified E26 transformation-specific 1 (ETS1) as a key transcriptional regulator in EM pathogenesis through integrative analysis of bulk and single-cell transcriptomic datasets.</p> Results <p>Across three independent transcriptome datasets and two validation cohorts, ETS1 expression was consistently elevated in endometriosis lesions, particularly in ovarian endometrioma. Single-cell RNA sequencing further revealed that ETS1 was predominantly expressed in endothelial cells and dynamically upregulated along the endothelial differentiation trajectory. Functional enrichment and pseudotime analyses indicated that ETS1 + endothelial cells exhibited enhanced angiogenic activity and vascular remodeling potential. Mechanistically, ETS1 amplified VEGF signaling by upregulating VEGFR1 and VEGFR2, while macrophage-derived VEGFA acted as the principal upstream activator within the lesion microenvironment. </p> Conclusions <p>Collectively, our findings delineate the VEGF–ETS1 axis as a central driver of pathological angiogenesis in endometriosis, positioning ETS1 as both a mechanistic hallmark and a promising therapeutic target for endometriosis.</p>