A series of novel 5-sulfonyl-indolin-2-ones were designed, synthesized, and screened for their antitumor activity on SGC-7901, A549, HCT116, and ECA-109 cell lines. Four compounds with the most potent antitumor activity were further determined as fibroblast growth factor receptor 2 (FGFR2) inhibitors. Among them, compound 2b was further identified to inhibit HUVECs tube formation. Many of the compounds exhibited more potent anticancer activity than Sunitinib, with compound 2b being the most active (IC50: 4.34, 6.87, 5.74 and 1.82 mM against human lung adenocarcinoma A549, human gastric cancer SGC-7901, human esophageal cancer ECA-109 and colorectal carcinoma HCT116 cell lines, respectively). Compounds 2b, 2c and 1b exhibited more potent kinase inhibitory activity than Quercetin dehydrate and Sunitinib. Compound 2b induced apoptosis in A549 cells and reduced HUVEC migration and tube formation in a dose-dependent manner. In summary, two series of 5-α,β-unsaturated sulfonyl-indolin-2-ones were synthesized and identified as potent inhibitors of angiogenesis, with compound 2b exhibiting high inhibitory activity against FGFR2 protein kinase as well as HUVECs tube formation.