Thirteen novel oleanolic acid (OA) derivatives were designed and synthesized with modification at positions of C-3, C-12 and C-28 of OA. Their structures were confirmed by MS, 1H NMR and elemental analysis. Their in vitro cytotoxicities against various cancer cell lines (SGC7901, MCF-7 and A549) were evaluated by MTT assay. The results indicated that the tested derivatives were found to have stronger cell growth inhibitory activity than OA. Among them, compounds II2 and II3 showed more potent cytotoxicity on MCF-7 and A549 tumor cells than gefitinib (positive control). They are worthy to be studied further.