This study aimed to elucidate the molecular impact of acute PM2.5 exposure (200 μg/mL, 24 h) on two NSCLC cell lines (A549 and NCI-H1975), each with distinct mutational backgrounds—A549 (KRAS-mutant, p53 wild-type) and NCI-H1975 (EGFR-mutant, p53-mutant). This evidence concerns the gene EGFR and non-small cell lung carcinoma.