A series of new quinoline derivatives were designed, synthesized and evaluated for antiproliferative activity against two cancer cell lines (MCF-7 and HCCLM-3) and a human normal cell line (HEK293T cells). Among them, 3-(2,7-dimethoxyquinolin-3-yl)-1-(4-methoxyphenyl)prop-2-en-1-one displayed the most inhibitory activity against MCF-7 and HCCLM-3 cells, which were equal and better than the positive control 5-fluorouracil (82.18% vs. 83.29%, 94.79% vs. 76.98%), respectively. Additionally, it had poor inhibitory activity (48.14%) against HEK293T cells, which displayed good selectivity for cancer cells. Therefore, 3-(2,7-dimethoxyquinolin-3-yl)-1-(4-methoxyphenyl)prop-2-en-1-one could be as a lead compound to develop more potent anticancer agents.