Cyclooxygenase (COX) inhibitors Indomethacin and its structural analogs Sulindac exhibit cell growth inhibition and apoptosis inducing activities in various cancer cell lines via COX independent mechanisms. In this study, the molecular structures of Indomethacin and Sulindac were used as starting scaffolds to design novel analogs and their effects on the proliferation of human cancer cells were evaluated. Compared to Indomethacin and Sulindac inhibiting cancer cell proliferation with IC(50)s of more than 1 mM, the derivatives displayed significantly increased activities. Especially, one of the Indomethacin analogs inhibited the growth of a series of cancer cell lines with IC(50)s around 0.5 μM-3 μM. Mechanistic investigation revealed that the new analog was in fact a tubulin inhibitor, although the parental compound Indomethacin did not show any tubulin inhibitory activity. Tubulin polymerization assay indicated this compound inhibited tubulin assembly at high concentrations, but promoted this process at low concentrations which is a very unique mechanism. The binding mode of this compound in tubulin was predicted using the molecular docking simulation.