Abstract: Chrysin was synthesized in five steps starting from 2,4,6–trihydroxyacetophenone via methylation, acylation, Baker-Venkataraman rearrangement, cyclization and deprotection.With chrysin as the lead compound,novel chrysin derivatives 8a-8u were designed and synthesized.The chemical structures of these compounds were confirmed by ¹H NMR, ¹³C NMR,IR and MS.Twenty-one new chrysin derivatives were prepared and their antitumor activities were evaluated by MTT method on HCT-116 (human colon cancer cell line),HeLa (human cervical carcinoma cell line), DU-145 (human prostate cell line), SGC-7901 (human gastric cancer cell line),and HEK-293(human embryonic kidney cell line).Among these derivatives, 5-hydroxy-2-phenyl-7-(2-(piperazin-1-yl) ethoxy)-4H-chromen-4-one ( 8o ) had the most potent antitumor activity against HCT-116, HeLa, DU-145, and SGC-7901 cells.