Several novel indirubin-based N-hydroxybenzamides, N-hydropropenamides and N-hydroxyheptanamides (4a-h , 7a-h , 10a-h) were designed using a fragment-based approach with structural features extracted from several previously reported HDAC inhibitors, such as SAHA (vorinostat), MGCD0103 (mocetinostat), nexturastat A and PXD-101 (belinostat). The biological results reveal that our compounds showed excellent cytotoxicity toward three common human cancer cell lines (SW620, PC-3 and NCI-H23) with IC values ranging from 0.09 to 0.007 µM . The cytotoxicity of the compounds was equipotent or even up to 10-times more potent than adriamycin and up to 205-times more potent than SAHA . Among the series of N-hydroxypropenamides, compounds 10a-d were the most potent HDAC inhibitors as well as cytotoxicity toward the cell lines tested . In addition, the strong inhibitory activites toward HDAC of our compounds were observed with IC values of below-micromolar range . Especially, compound 4a inhibited HDAC6 with an IC value of 29-fold lower than that against HDAC2 isoform . Representative compounds 4a and 7a were found to significantly arrest SW620 cells at G0/G1 phase . Compounds 7a and 10a were found to strongly induce apoptosis in SW620 cells . Docking studies revealed some important features affecting the selectivity against HDAC6 isoform . The results clearly demonstrate the potential of the indirubin-hydroxamic acid hybrids and these compounds should be very promising for further development.