Lung cancer is considered the leading cause of cancer-related death worldwide. About 80% to 85% of lung cancers and the majority of cancer-related deaths worldwide were caused by the prominent subtype of non-small cell lung cancer. NSCLC displays several genetic abnormalities including the tumor suppressor gene (TP53). This study's objective was to determine if the TP53 codon 72 rs1042522 polymorphisms play a role in NSCLC susceptibility. Case-control research was done at the Mansoura university oncology center. The study included 124 patients suffer from NSCLC, and the control group included 124 healthy-matched volunteers. DNA from the blood was collected. To genotype single-nucleotide variations, ARMS-PCR was employed. The genetic study of TP53 rs1042522 (codon 72) showed Significant correlations among NSCLC cases and a larger percentage of AP, AP+PP genotypes, and P allele, (p<0.05 for each), with a risk to develop NSCLC (OR>1 for each). AP+PP genotype was significantly associated with lower vascular invasion when compared to the AA genotype. Otherwise, no significant association was found regarding TP53 genotypes with Tumor location, histopathology, or grade among all studied cases. In conclusion, our results showed that TP53 codon 72 rs1042522 polymorphism may be associated with the development of advanced NSCLC in Egyptians and can use as a prognostic biomarker for lung cancer.