In this study, a series of novel N-(4-phenylthiazol-2-yl) cinnamamide derivatives (7a~8n) were synthesized and evaluated for their anti-proliferative activities in vitro by MTT assay and the possible antitumor mechanism was also explored. The SAR analysis showed that the steric effect played an important role on the anti-tumor activity. The most potent analogue 8f showed excellent inhibitions on the K562, Bel7402, A549 and Jurkat cells ranging from sub-micromolar to nanomolar concentration. Compound 8f inhibited Jurkat cells with IC50 value of 0.035 µM with no apparent toxicity in different non-cancerous cells. Furthermore, it was suggested that the possible mechanism of 8f might be associated with inducing cancer cells apoptosis on the results of flow cytometer analysis and Hoechst 33358 staining assays.