The overexpression of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) is widely acknowledged as having diagnostic and prognostic significance in breast cancer, and despite lapatinib (EGFR/HER2 dual inhibitor) achieves high cure rates in most breast cancer cases, many patients develop resistance and don’t respond to it. Thus, the design of new approaches of EGFR/HER2 inhibitors for the management of breast cancer is an urgent need. Herein, novel pyrazolo [3,4-d]pyrimidine derivatives tethered to hydrazones, thiazoles, 1,3,4-thiadiazoles and 1,2,4-triazoles were developed and evaluated as EGFR/HER2 dual inhibitors. The thiazole bearing compound 10f achieved the highest EGFR/HER2 dual inhibitory potential with IC50 values of 0.09 and 0.08 μM respectively, along with better cytotoxic IC50 levels against different cancer cell lines such as HePG-2 (3.90 μM), HCT-116 (7.35 μM) and MCF-7 (2.84 μM). Compound 10f likewise achieved substantial elevated cytotoxic activities against lapatinib-resistant breast cancer cell lines SKBr3, BT474 and MDA-MB-453. The Flow Cytometry for the compound 10f was accomplished against MCF-7 breast cancer cell line, and the results demonstrated the capability of it to induce apoptosis and arrest the MCF-7 cell cycle in the G0/G1 phase. The in-silico docking investigations exposed that, the pyrazolo [3,4-d]pyrimidine bearing thiazole 10f demoed high affinity for the ATP-binding domains of both EGFR and HER2 with considerable binding scoring of 4.768 and 8.572 Kcal/mol respectively, comparable with the lapatinib reference ( 5.599 and 7.442 Kcal/mol). Finally, the stabilities of the formed complexes of compound 10f with both EGFR and HER2 targets, were considered by a distinctive atomistic 200 ns dynamic simulation approach. The MD simulation trajectories were operated and approved the stability of the formed complexes under the dynamic solvated conditions.