Chalcones 1~8 and 5‐deoxyflavonoids 9~22 were synthesized in good yields by aldol condensation, Algar‐Flynn‐Oyamada reaction, glycosidation, and deacetylation reaction, respectively, starting from 2‐acetyl phenols substituted by methoxy or methoxymethoxy group and appropriately benzaldehydes substituted by methoxy, methoxymethoxy group, or chlorine. Among them, 13 and 17~22 are new compounds. The cytotoxicity bioassays of these chalcones and 5‐deoxyflavonoids were screened using the sulforhodamine B (SRB) protein staining method, and the results showed that compounds 2, 4, 5, 6, 10, 15, and 19 exhibited moderate cytotoxicity against the cancer cell line of MDA‐MB‐231, U251, BGC‐823, and B16 in comparison with control drugs (HCPT, Vincristine, and Taxol).