By varying the substituents (R(1)) at the indolin-2-one scaffold, a series of indolin-2-one derivatives bearing 4-phenylpiperazine-1-carbothiohydrazide moiety at the C3-position were synthesized and evaluated for their antiproliferative activity against three human cancer cell lines. We further selected the 5-chloroindolin-2-one moiety for the extension to another series of compounds by varying the substituents (R(2)) at the phenyl group connected with the piperazine ring. Among all the compounds synthesized, 6d and 6l were most potent with IC50 values of 3.59 and 5.58 μM, respectively against A549 lung cancer cells, while 5f and 6l possessed IC50 values of 3.49 and 4.57 μM, respectively against HCT-116 colon cancer cells which were comparable to that of Sunitinib, an indolin-2-one derivative in cancer therapy.