Objectives: Antibody-drug conjugates (ADCs) are promising therapeutic biologics for cancer treatment, and Mirvetuximab soravtansine (MIRV) is currently the only FDA-approved ADC for treating folate receptor alpha (FRalpha) positive platinum-resistant epithelial ovarian cancer (PROC). Results from the Phase 3 EV-302/KEYNOTE-A39 trial indicate that the combination of Nectin-4-directed ADC Enfortumab Vedotin-ejfv (anti-Nectin-4 ADC) and pembrolizumab yields better treatment outcomes than platinum-based chemotherapy in patients with metastatic urothelial carcinoma. The study aims to investigate the potential of repurposing anti-Nectin-4 ADC as a therapeutic strategy for epithelial ovarian cancer (EOC), and to explore effective combination therapies targeting Nectin-4-positive EOC tumors. Methodology: Nectin-4 expression in EOC was validated through multiplex immunohistochemistry (MIHC) in our institutional tissue cohort and corroborated in independent public datasets. In vitro efficacy of anti-Nectin-4 ADC was evaluated using cytotoxicity, apoptosis, and clonogenic assays in EOC cell lines. Anti-tumor activity was investigated in patient-derived organoid models and xenograft models. Result: Nectin-4 expression in EOC is heterogeneous but generally elevated compared to matched normal tissues. The Nectin-4-targeted ADC demonstrated significant cytotoxicity in Nectin-4-positive EOC cell lines. Both in silico and in vitro analyses revealed that Nectin-4-positive tumors are sensitive to two FDA-approved compounds, potentially due to dysregulated fatty acid metabolism. In vivo studies confirmed that anti-Nectin-4 ADC monotherapy effectively suppressed tumor growth, and combination treatments further enhanced survival outcomes. Conclusion: This study demonstrates the therapeutic potential of Nectin-4-targeted agents in preclinical models of Nectin-4-positive EOC, supporting their advancement toward clinical translation. Additionally, the findings suggest that repurposing Nectin-4-guided combination therapy could expand and enhance treatment options for EOC.