In an attempt to develop potent and selective anti-tumor agents, two novel series of artemisinin-chalcone hybrids were designed, synthesized and screened for their antitumor activities against HT-29, A549, MDA-MB-231, HeLa and H460 cell lines in vitro. Nearly all of the tested compounds showed significantly increased anti-tumor activity compared with the corresponding dihydroartemisinin (DHA). Most of the title compounds displayed good selectivity toward HT-29 and HeLa cell lines with IC₅₀ values ranging from 0.09 to 0.85 µM. Among them, the most promising compound 9c (IC₅₀) range of 0.09-0.93 µM) was 10.5- to 70-times more active than DHA (IC₅₀ range of 5.6-15.6 µM) respectively.