A novel series of 2-substituted thio-7-chloroquinazolin-4(3H)-one derivatives was rationally designed, synthesized, and evaluated as dual inhibitors of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor-2 (VEGFR-2) with potential anticancer activity. Structural optimization was achieved through the incorporation of diverse linkers and pharmacophoric motifs, including aryl amides, hydrazones, chalcones, and heterocyclic moieties, to target key kinase binding domains. In vitro screening against the NCI-60 human tumor cell line panel revealed several compounds with broad-spectrum antiproliferative activity, among which the chalcone derivative (11a) emerged as the most potent. Compound (11a) exhibited low micromolar GI₅₀ values, high selectivity towards cancer cells over normal cells, and strong dual inhibition of EGFR and VEGFR-2 in the nanomolar range. Mechanistic studies demonstrated that (11a) induced G₁/S phase cell cycle arrest, activated apoptotic pathways, suppressed receptor phosphorylation, and promoted PARP-1 cleavage. Notably, (11a) retained inhibitory activity against clinically relevant EGFR resistance mutants, including C797S. Molecular docking and dynamics simulations indicated stable, favorable binding within the ATP-binding sites of both kinases. Collectively, these findings identify compound (11a) as a promising dual-target anticancer lead warranting further preclinical investigation.