Malignant melanoma (MM) represents the most life-threatening skin cancer worldwide, with a narrow and inefficient chemotherapeutic arsenal available in advanced disease stages. Lupeol (LUP) is a triterpenoid-type phytochemical possessing a broad spectrum of pharmacological properties, including a potent anticancer effect against several neoplasms (e.g., colorectal, lung, and liver). However, its potential as an anti-melanoma agent has been investigated to a lesser extent. The current study focused on exploring the impact of LUP against two human MM cell lines (A375 and RPMI-7951) in terms of cell viability, confluence, morphology, cytoskeletal distribution, nuclear aspect, and migration. Additionally, the in ovo antiangiogenic effect has been also examined. The in vitro results indicated concentration-dependent and selective cytotoxicity against both MM cell lines, with estimated IC50 values of 66.59 ± 2.20 for A375, and 45.54 ± 1.48 for RPMI-7951, respectively, accompanied by a reduced cell confluence, apoptosis-specific nuclear features, reorganization of cytoskeletal components, and inhibited cell migration. In ovo, LUP interfered with the process of angiogenesis by reducing the formation of neovascularization. Despite the potential anti-melanoma effect illustrated in our in vitro-in ovo study, further investigations are required to elucidate the underlying LUP-induced effects in A375 and RPMI-7951 MM cells.