Cancer prevention has become a significant public health concern in the 21st century, ranking as the second leading cause of global mortality following cardiovascular diseases. Despite prominent advancements in treatment, addressing cancer remains a substantial public health challenge, necessitating precise interventions tailored to diverse cancer types. The targeting of Epidermal Growth Factor Receptor (EGFR) has emerged as a fundamental strategy in modern cancer therapy due to its critical role in oncogenesis. Chalcones, a subclass of flavonoids, are promising anticancer agents due to their ability to target multiple cellular pathways implicated in cancer progression. The presence of α, β-unsaturated carbonyl moiety is a key structural feature attributed to their biological activity. This study presents an efficient synthesis approach for chalcone derivatives 4a-f designed from natural thymol. The synthesized compounds were further characterized by HRMS, 1H and 13C NMR spectral data, and further evaluated for in silico studies through molecular docking, molecular dynamic simulation, and ADMET screening. All the designed compounds 4a-f displayed favourable physicochemical properties and ADMET profiles. Molecular docking revealed favourable interactions between compounds 4a-f and the EGFR target protein. Compound 4d (p-nitro) and 4b (p-methyl) showed the more favourable docking score with low energy conformation (-8.02 kcal/mol), (-7.42 kcal/mol) respectively compared to the standard drug Gefitinib. Molecular dynamic simulations confirmed the stability of compounds 4d and 4b, exhibiting consistent structural stability in ligand-protein complexes throughout the 100 ns simulation. Acceptable RMSF values for amino acid residues indicated structural integrity and a stable protein-ligand interaction. The study identified 4d and 4b as promising leads for targeting EGFR.