Epidermal Growth Factor Receptor (EGFR) is crucial for cancer cell growth, survival, and resistance. Inflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) also help tumors grow and evade the immune system. Developing multi-targeted inhibitors that hit both cancerous and inflammatory pathways has strong therapeutic potential. This study aims to design, create, and test novel series of pyridone-based derivatives serving as dual inhibitors of EGFR signaling pathways with anti-inflammatory effects by suppressing IL-6 and TNF-α. We synthesized and structurally characterized a set of novel pyridone derivatives. We checked their physicochemical and pharmacokinetic properties using in silico ADMET profiling. We evaluated the anticancer activity of the compounds through the MTT assay, testing viability and cytotoxicity in MCF-7 (breast) and A549 (lung) cancer cell lines. We further assessed selected compounds for their EGFR inhibitory effects and cytokine suppression. We conducted flow cytometry (Annexin V/PI staining) to evaluate apoptosis induction. Some of the novel compounds showed high binding affinity to EGFR in docking studies. Among these, compound 5h showed potent anticancer activity on both tested cell lines A549 and MCF7 with an IC50 of 9.2 μM and 8.2 μM respectively also it significantly reduced IL-6 and TNF-α levels in A549 cells, also showed promising ADMET profiles. Flow cytometry confirmed apoptosis induction in a dose-dependent manner. We performed molecular docking to evaluate the binding affinity against EGFR and related inflammatory targets. DFT calculations were performed to analyze molecular reactivity through HOMO/LUMO and molecular electrostatic potential (ESP) studies. ESP map analysis supports theoretical descriptors and confirms that compound 5h is the most biologically active candidate among the synthesized derivatives.