This study aimed to synthesize four new semisynthetic derivatives of natural oleanolic acid (OA) and, based on an analysis of their cytotoxic and anti-proliferative effects against human MeWo and A375 melanoma cell lines, select those with anti-cancer potential. We also screened the treatment time with the concentration of all four derivatives. We synthesized oxime 2 and performed its acylation with carboxylic acids into new derivatives3a, 3b, 3cand3daccording to the methods previously described. Colorimetric MTT and SRB assays were used to measure the anti-proliferative and cytotoxic activity of OA and its derivatives3a,3b,3cand3dagainst melanoma cells. Selected concentrations of OA, the derivatives, and different time periods of incubation were used in the study. The data were analyzed statistically. The present results revealed the possible anti-proliferative and cytotoxic potential of two selected OA derivatives3aand3b, on A375 and MeWo melanoma cells, especially at concentrations of 50 μM and 100 μM at 48 h of incubation (p< 0.05). Further studies will be necessary to analyze the proapoptotic and anti-cancer activities of3aand3bagainst skin and other cancer cells. The bromoacetoxyimine derivative (3b) of OA morpholide turned out to be the most effective against the tested cancer cells.