A total of 16 targeted oleanolic acid-uracil/thymine hybrids were designed and synthesized as potential cytotoxic agents. Most IC50 values were under 10.0 μM, even with some of them were under 0.1 μM in vitro against tested cells (Hep-G2, A549, BGC-823, MCF-7 and PC-3). These hybrids displayed much more potent inhibitory activities compared with oleanolic acid and commercial anticancer drug 5-fluorouracil (5-FU). The combination of fluorescence staining observation and flow cytometric analysis suggested that selected oleanolic acid-uracil hybrid 6a possessed clear cell apoptosis inducing effects. And the underlying mechanisms for the antitumor activity were associated with loss of mitochondrial membrane potential, arrest Hep-G2 cell line at G1 phase and activate effector caspase-3/9 to trigger cell apoptosis.