The aim of the study was to compare the effects of three natural bioactive compounds (and their combinations) on normal vs. tumour-transformed mouse cells. The cytotoxic effect of Aeruginosin-865 (Aer), capsaicin (Cap), resveratrol (Res) and their combinations was evaluated on normal hepatocytes (AML) and tumour cells derived from livers (Hepa) and kidneys (Renca). Various concentrations from 25 to 200 μM of tested substances were used. Only the Aer + Res combination and a low concentration of Res had a significant cytotoxic effect on Hepa and Renca and no significant cytotoxic effect on AML. Cap had a significant cytotoxic effect on all tested cell lines, but tumour-derived cells showed higher resistance than AML. A significantly increased cytotoxicity was found in the combination of Cap + Res compared to each substance alone. All types of cells showed similar sensitivity to the cytotoxic effect of Cap + Res. Because of a possible hepatotoxic effect, we recommend further investigations into side-effects of Cap + Res. No cytotoxic effect was described in Cap + Aer or in Aer alone. Only substances with a significant cytotoxic effect on tumour cells and no cytotoxic effect on normal cells can be potentially used in anticancer treatment. According to the results, only Res or the combination of Aer + Res can be recommended for further evaluation in the process of new anticancer drug development. The potential hepatotoxic effect of Cap + Res can significantly limit the utilisation of these substances in anticancer treatment.