It has been demonstrated that both cucurbitacin I (Cu I) and caffeic acid phenethyl ester (CAPE) have anticancer activities. The current study aimed to examine the proliferation, migration, and colony formation actions of Cu I and CAPE on MCF-7 and MDA-MB-231 human breast cancer cells. The antimigration, antiproliferative, and colony inhibition effects of different dosages of Cu I, CAPE, and Cu I + CAPE on cells were determined by the 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) cell viability assay, wound healing, and colony formation assays, respectively. Compared with single treatment, combination of 2 bioactive compounds enhanced the anticancer activity. When Cu I and CAPE were combined, a strong inhibitor effect was shown on cell growth, colony formation, and cell migration compared with the compounds used singly. The concomitant treatment with Cu I and CAPE showed stronger antiproliferative activities on both MCF-7 and MDA-MB-231 cells compared with individual treatment with either Cu I or CAPE. Caffeic acid phenethyl ester is a specific inhibitor of Nuclear factor-kappa B (NF-kappa B). It shows anticancer activity depending on this inhibition. It is a bioactive phenolic compound that is derived from propolis. Cucurbitacin I is a selective Januskinase/signal transducer and a transcription-3 signal pathway inhibitor. Combination of these 2 natural anticancer compounds is beneficial in the treatment of cancer, as well as the side effects associated with classical chemotherapeutics not being observed with the use of these compounds.