The dual targeting of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) represents an effective approach for cancer treatment. The current study involved the design, synthesis, and biological evaluation of a new series of purine-containing hydrazones, - (,), as anticancer agents targeting EGFR and HER2 kinases. The proposed compounds were initially screened in silico using molecular docking to investigate their binding affinity to the active sites of EGFR and HER2 kinase domains. Subsequently, the compounds were synthesized and evaluated in vitro for their antiproliferative activity, using the MTT assay, against the various cancer cell lines A549, SKOV-3, A2780, and SKBR-3, with lapatinib as the reference drug. The most active derivatives were then examined to determine their inhibitory activity against EGFR and HER2 kinases. Among the assessed compounds, significant antiproliferative activity was demonstrated by , , and . exhibited substantial anticancer efficacy against A549 and SKBR-3, with IC values of 0.81 µM and 1.41 µM, respectively. This activity surpassed lapatinib, which has an IC of 11.57 µM on A549 and 8.54 µM on SKBR-3 cells. Furthermore, , , and exhibited superior EGFR inhibitory efficacy compared with lapatinib (IC = 0.13 µM), with IC values of 0.08, 0.06, and 0.07 µM, respectively. Regarding HER2, demonstrated the greatest potency with an IC of 0.03 µM, equipotent to lapatinib (IC = 0.03 µM). Flow cytometry analysis of A549 cells treated with and indicated their ability to arrest the cell cycle during the G1 phase and to trigger cellular apoptosis. Compounds , , and represent intriguing candidates for the development of an anticancer agent targeting EGFR and HER2 kinases.