We recently reported that the chalcone-based compounds DK-13 and DK-14, developed by our group, impair the growth of triple-negative breast cancer [24]; thus, we herein explore the outcome of these two new compounds on two HER2-positive breast cancer cell lines in addition to angiogenesis of the chorioallantoic membrane (CAM) model and their underlying mode of action. The gene discussed is ERBB2; the disease is breast cancer.