Malignant melanoma has a steadily increasing incidence, but treatment options are still limited, and the prognosis for patients, especially for men, is poor. To investigate whether targeting estrogen receptor (ER) signaling is a valid therapeutic approach, we retrospectively analyzed ER gene expression profiles in 448 patients with melanoma. High ERα gene (ESR1) expression was associated with improved overall survival (hazard ratio = 0.881; 95% confidence interval = 0.793-0.979; P = 0.018) and increased with tumor stage, whereas ERβ gene (ESR2) expression did not change with tumor progression. This seemingly protective function of ERα led us to speculate that specific targeting of ERβ has a therapeutic benefit in malignant melanoma. An ERβ-selective ER modulator with nitric oxide‒releasing moiety (nitric oxide‒releasing selective ER modulator 4d [NO-SERM 4d]) significantly reduced the prometastatic behavior of two melanoma cell lines (A2058 and MEL-JUSO). Epithelial‒mesenchymal transition in melanoma is consistent with a switch from E- to N-cadherin expression, mediating the invasive phenotype. NO-SERM 4d reduced N-cadherin expression and impaired spheroid formation in A2058 cells. In addition, the growth of A2058 spheroids was significantly reduced, confirming the antitumorigenic potential of NO-SERM 4d. Targeting ERβ signaling combined with targeted nitric oxide release represents a promising therapeutic approach in malignant melanoma that has the potential to prevent metastatic spread and reduce tumor growth.