A novel series of indole-2-carbohydrazide derivatives were synthesized, characterized, and evaluated for their antiproliferative activities against two cancer cell lines, HCT116 and SW480, and a normal human fetal lung fibroblast cell line, MRC-5. Among this series, compound 24 f displayed potent cytotoxic activities in vitro against HCT116 and SW480 cell lines with GI50 values of 8.1 and 7.9 μm, respectively, and was inactive against MRC-5 cells. The newly synthesized compounds were also evaluated for anti-angiogenesis capabilities by chick chorioallantoic membrane, human umbilical vein endothelial cell (HUVEC) migration, and endothelial microtubule formation assays. Moreover, the effects of 24 f on the vascular endothelial growth factor receptor-2 and the signaling pathway in HUVECs indicated that this compound inhibits VEGFR-2 and its downstream related proteins. These results indicate that compound 24 f, as well as the other derivatives, are promising inhibitors of angiogenesis.