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Endometriosis is a chronic systemic disease affecting ~10% of women, yet its genetic basis and molecular mechanisms remain poorly understood. Hence, here we conducted a genome-wide association study of endometriosis and adenomyosis in ~1.4 million women, including 105,869 cases, aiming to expand loci discovery across ancestries, dissect symptom-specific effects and integrate multi-omic data. We identified 80 genomic regions associated with endometriosis risk, including 37 new loci, of which 5 are also associated with adenomyosis. We identified putative causal variants underlying over 50 of these associations. Transcriptomic, epigenetic and proteomic analyses across tissues linked endometriosis risk to pathways involved in cell differentiation, immune and hormonal regulation, tissue remodeling and inflammation. Drug-repurposing analyses highlighted potential treatments currently used for breast cancer, contraception and preterm birth prevention. Endometriosis polygenic risk interacted with abdominal pain, anxiety, migraine and nausea. This study advances understanding of genetic risk factors for endometriosis and provides molecular support for several hypotheses on its pathogenesis.