Targeting the epidermal growth factor receptor (EGFR) remains a validated strategy for the treatment of lung cancer. In pursuit of potent EGFR inhibitors against non–small cell lung cancer (NSCLC), a novel series of nicotinamide derivatives was rationally designed, synthesized via a Pd-catalyzed Buchwald–Hartwig cross-coupling reaction, and comprehensively evaluated for their biological activity. The synthesized compounds exhibited promising cytotoxicity against the A549 cell line, with IC₅₀ values ranging from 8.90 to 39.69 µM. Specifically, molecule 5 demonstrated superior antiproliferative efficacy (8.90±1.6μM) than the reference drug Gefitinib (IC₅₀ = 9.22µM). Notably, compound 5 displayed significantly reduced cytotoxicity toward non-cancerous cell lines, suggesting a favorable selectivity profile. Moreover, mechanistic studies on molecule 5 demonstrated enhanced clonogenic survival, modulated intracellular ROS levels, substantially enhanced apoptotic cell populations, and significant EGFR inhibition efficacy (0.9 μM). Interestingly, the performed combination treatment of molecule 5 with Gefitinib demonstrated 1.26-fold enhanced antiproliferative efficacy compared to compound 5 and Gefitinib alone over the A549 cell line. On the other hand, Molecular docking studies revealed strong binding affinities toward the T790M mutant EGFR protein, primarily mediated through hydrogen bonding, hydrophobic, and electrostatic interactions within the receptor’s hydrophobic pocket, and they were corroborated through MD simulation and DFT studies, confirming the stable ligand-receptor interaction as well as chemical reactivity parameters. Furthermore, in silico ADME analyses predicted favorable pharmacokinetic and physicochemical properties within acceptable ranges for drug-likeness and human usage. Collectively, these findings highlight the synthesized nicotinate-based molecules as promising lead candidates for the development of next-generation EGFR inhibitors to overcome drug resistance in NSCLC.