Despite advances in early detection and conventional therapies, non-smallcell lung cancer (NSCLC) remains one of the leading causes of cancerrelated mortality worldwide. It is frequently diagnosed at an advanced stage, resulting in a poor overall prognosis. A deeper understanding of the molecular mechanisms underlying NSCLC is essential for developing more effective therapeutic strategies. Human interferon-gamma (hIFN-γ) is a cytokine known for its anti-tumor properties; however, its precise role and mechanism of action in lung cancer remain incompletely unclear. This study aimed to investigate the effects of hIFN-γ on two NSCLC cell lines, A549 and H2170. The cytotoxic and pro-apoptotic potential of hIFN-γ was assessed by evaluating DNA fragmentation using the Comet assay, apoptosis through flow cytometry, and p53, p21, caspase-3, and Bcl-2 gene expression using quantitative PCR. Both liposomal (L) and naked (N) formulations of hIFN-γ significantly induced DNA damage compared with the untreated controls. Gene expression analysis revealed the downregulation of the anti-apoptotic marker Bcl-2 and the upregulation of p53, p21, and caspase-3, indicating p53-mediated apoptosis and p21-induced cell cycle arrest. Notably, the liposomal formulation (L) exhibited stronger proapoptotic effects than the naked form (N), suggesting the enhanced therapeutic potential of the liposomal delivery system in NSCLC treatment.