The thiazole ring closure of thiosemicarbazones with α-bromo-4-substituted acetophenones was carried out to generate aminothiazole analogs (A1-A16).Exptl. methods were used to characterize the developed compounds, including HRMS, 1H, 13C NMR, and elemental anal.Single-crystal XRD investigations have verified the compound A5 crystal structure.All the synthesized hybrid compounds underwent screening for their anticancer activity against various cancer cell lines, encompassing human breast adenocarcinoma (MCF-7) and human lung adenocarcinoma (A549), as well as normal human breast cell (MCF-10A).The compounds A2, A5, and A8 exhibited excellent anticancer activity against MCF-7 and A549 cancer cell lines compared to the reference drug Erlotinib.Later, in vitro, EGFR results revealed that compared to the reference drug Erlotinib (IC50 value = 0.42 ± 0.04 μM), compounds A2, A5 and A8 displayed the highest tyrosine kinase EGFR inhibitory potency with IC50 values of 1.38 ± 0.11 μM, 0.88 ± 0.05 μM and 1.86 ± 0.12 μM, resp.Furthermore, in silico mol. docking studies on EGFR (PDB ID: 4HJ0) protein revealed that the potent ligands exhibited higher affinity with an active pocket of receptors showing strong hydrogen bond interactions.The compounds′ electronic behavior, stable geometries, MEP surfaces, and FMO anal. were investigated employing d. functional theory (DFT) at the B3LYP level with a 6-311G(d, p) basic set.An in silico ADMET study was also performed to predict the pharmacokinetic and toxicity profile of synthesized compounds, which expressed good oral drug-like behavior and non-toxic nature.Further, the photophys. properties (UV and fluorescence) of the compounds were discussed.