A novel chrysin derivative, hydroxyethyl chrysin (HE-chrysin), was previously discovered by irradiation technology, which exerted greater anti-inflammatory and anti-cancer activities than original chrysin. Here, we aimed to explore whether HE-chrysin exhibits anti-oxidant and anti-melanogenic potential using B16F10 melanoma cells and molecular docking analysis. According to the DPPH, ABTS, and FRAP assays, HE-chrysin exhibited greater antioxidant ability and decreased cellular H₂O₂-induced reactive oxygen species level compared with the original chrysin. At a concentration of 2.5 μM, HE-chrysin considerably attenuated IBMX-induced melanin generation by inhibiting tyrosinase activity and tyrosinase expression without inducing cytotoxicity. Further, docking results indicated that HE-chrysin inhibited enzymatic activity by chelation copper ions at the active site of tyrosinase. These findings highlight the potential of HE-chrysin as an anti-melanogenic and anti-oxidant candidate for dermatological therapy.