In this study, we designed and synthesized a series of both known (4a–4o, 4r–4s) and novel (4p–4q, 4t–4v) O-alkylated (E)-chalcone derivatives, evaluating their anticancer properties against various cancer cell lines, including HCT-116, MDA-MB-231, Hela, and MCF-7, and a non-cancer cell line, WI-38, as well as their effects on specific enzymes (EGFR, HER2, VEGFR-2, and CDK2) and anti-estrogenic activity. Here, ERBB2 is linked to cancer.