Ten novel artemisinin derivatives containing sulfur atoms were designed and synthesized and their structures were confirmed by (1)H NMR, (13)C NMR and HRMS technologies in this study. All compounds were reported for the first time. The in vitro cytotoxicity against PC-3, SGC-7901, A549 and MDA-MB-435s cancer cell lines was evaluated by MTT assay. Compounds 4a and 4f displayed potent antitumor activity against PC-3, SGC-7901 and A549 cells with IC50 ranging from 1.6 to 30.5 μM, which values are compared to that of 5-FU (IC50 from 6.8 to 42.5 μM). Compounds 4a and 4f showed high specificity towards human lung cancer A549 cells compared to normal human hepatic L-02 cells with selectivity index of 16.1 and 50.1 respectively. Our promising findings indicated that the compounds 4a and 4f could stand as potential lead compounds for further investigation.