Lung cancer, particularly non-small cell lung cancer (NSCLC), remains a leading cause of cancer-related mortality. Mutations in the tumor suppressor protein p53 contribute to tumor progression and chemoresistance, making p53 reactivation a promising therapeutic strategy. PRIMA-1(Met), a small molecule designed to restore mutant p53 function, has shown potential in various cancers. This study investigates the cytotoxic effects of PRIMA-1(Met), alone and in combination with etoposide, on NSCLC cell lines. Human NSCLC cell lines A549 (p53-wild type) and NCI-H1975 (p53-mutant) were treated with PRIMA-1(Met) and/or etoposide. Cell viability was assessed using the WST-1 assay at 24, 48, and 72 hours. Statistical analyses were performed using one-way ANOVA followed by Tukey’s test. PRIMA-1(Met) exhibited a dose- and time-dependent cytotoxic effect, with NCI-H1975 cells showing greater sensitivity compared to A549 cells (p<0.001). Etoposide treatment alone induced cytotoxicity, but its combination with PRIMA-1(Met) significantly enhanced cell death in both cell lines, particularly in p53-mutant NCI-H1975 cells (p<0.001). These findings suggest that PRIMA-1(Met) is more effective in p53-mutant NSCLC cells and that its combination with etoposide enhances its therapeutic potential. This study supports further investigation into PRIMA-1(Met) as a targeted therapy for p53-mutant NSCLC, particularly in combination with standard chemotherapy.