In continuation of our previous work, novel sulphonamide–thiazole hybrids were synthesized and evaluated for anticancer activity against NCI–H226 lung carcinoma cells, with WI-38 fibroblasts as a normal control. Among the tested compounds, fluoro-substituted compound 14 exhibited the highest potency (IC₅₀ = 16.10 μg/mL) and selectivity (SI = 183.79), while halogen- and nitro-substituted analogs (4–6) showed moderate activity. Quantum mechanical studies using DFT (B3LYP/6-311G(d,p), SMD solvent) rationalized the observed SAR, highlighting the role of electronic and steric effects in modulating activity. Molecular docking revealed stronger binding of compound 14 to EGFR (−8.2 kcal/mol) than TP53 (−7.1 kcal/mol), suggesting EGFR as its primary target, with TP53 interactions supporting apoptotic signalling. ADMET predictions indicated favourable drug-likeness, low toxicity, and non-mutagenicity. Molecular dynamics simulations over 100 ns confirmed that compound 14 forms highly stable complexes with both EGFR and TP53, preserving secondary structures, and consistent hydrogen-bonding and hydrophobic interactions, with MM-GBSA free energies of ~ –75 kcal mol⁻¹. Free energy landscape and principal component analyses demonstrated conformational adaptability and long-term stability. Collectively, these results identify compound 14 as a potent, selective, and energetically favourable dual-target anticancer agent, providing a strong mechanistic foundation for further preclinical development.