A number of novel furo[2,3-b]quinoline derivatives were designed and synthesized by introducing benzyl ether, benzoate, and benzenesulfonate to 6-position of furo[2,3-b]quinoline and their chemical structures were confirmed by ESI-MS, 1H NMR, and 13C NMR spectra. All target compounds were evaluated in vitro against four human cancer cell lines (HCT-116, MCF-7, U2OS, and A549) by MTT method. Cytotoxic assay showed that compounds 8a, 8e, 10a, 10b, and 10c exhibited more potent cytotoxicities compared to 2-bromine-6-hydroxy-furo-[2,3-b]quinoline (7). Compound 10c exhibited higher antiproliferative activity (IC50 values ranging from 4.32 to 24.96 μm) against four human cancer cell lines (HCT-116, MCF-7, U2OS, and A549) and weak cytotoxicity on normal cell HL-7702, which suggested that 10c might be an ideal anticancer candidate. Compounds 8a, 10a, 10b showed good selectivities to MCF-7 and HCT-116, which could be considered as ideal selective candidates for further study. The SARs showed that the introduction of the benzyl ether and benzenesulfonate could significantly improve cytotoxicities, while the benzoate failed to enhance potency obviously.