Chalcones from medicinal plants are attractive starting points for anticancer lead discovery, and this study aimed to improve the anti-NSCLC potential of 2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone (DMC) from Syzygium nervosum through targeted structural modification and mechanistic computational analysis. Air-dried seeds were extracted with CH₂Cl₂, DMC was purified by silica gel chromatography and crystallization, and its structure was confirmed by HRMS, FTIR and NMR; 4′-O-derivatization with meta– or para–[(bromomethyl)phenyl]methyl groups afforded derivatives 2a and 2b (89–92% yield). Antiproliferative activity and cytotoxicity were evaluated by MTT assay in NSCLC cell lines (A549, NCI-H460) and normal lung fibroblasts (MRC-5) with osimertinib as a reference. Derivatives 2a and 2b showed enhanced activity against NCI-H460 (IC₅₀ = 7.97 ± 0.62 µM and 7.91 ± 2.77 µM) while remaining weak against A549, and they were less cytotoxic to MRC-5 (IC₅₀ ≥ 50 µM and 16.08 ± 0.45 µM) than osimertinib (IC₅₀ = 3.43 ± 0.35 µM). DFT/MEP analyses, docking to wild-type EGFR (1M17; redocking RMSD 1.228 Å), and 500 ns × 3 replica MD simulations supported improved EGFR binding stability for 2a/2b, with MM/GBSA indicating favorable binding free energies (−28.78 ± 6.11 and −21.99 ± 9.39 kcal/mol). Overall, 4′-O-functionalization of DMC generated lead derivatives with improved in vitro activity in NCI-H460 and computationally supported target–ligand stabilization.