A series of N-(4-hydroxy-3-mercaptonaphthalen-1-yl)amides were synthesized and investigated for their in vitro antiangiogenic activity. Among these compounds, 6d, which possesses an ortho-nitro group at the benzene ring, exhibited potent inhibitory effect on the proliferation of HUVECs, A549, K562, PC-3, HCT116, MDA-MB-231 and MCF-7 cells (IC50 = 5.34, 40.53, 10.81, 52.52, 10.19, 21.37 and 2.81 μM, respectively). Meanwhile, compound 6d inhibited in vitro angiogenesis markedly in both HUVECs tube formation assay and the rat thoracic aorta rings test. Further kinase assay study showed that compound 6d had good VEGFR2, ALK, AKT1 and ABL inhibitory activities and moderate EGFR and PDGFR-β inhibitory activities. The data supports the further investigation of this class of compounds as potential antiangiogenic and anticancer agents.