Background <p>Lung cancer remains the leading cause of cancer-related deaths worldwide. Despite advances in diagnostics and treatment, most patients are diagnosed at advanced stages. Genetic variants such as single nucleotide polymorphisms (SNPs) may improve early detection and risk prediction. This study investigated the association of PPAR-γ rs1801282 and MTRR rs162036 polymorphisms with non-small cell lung cancer (NSCLC) susceptibility in Egyptians and further evaluated their role through a meta-analysis.</p> Methods <p>A case–control study was conducted including 127 NSCLC patients and 138 age- and sex-matched healthy controls. Genotyping of PPAR-γ rs1801282 and MTRR rs162036 variants was performed using the T-ARMS-PCR method. Logistic regression, stratified and multivariate analyses, and bioinformatics approaches were applied to assess genetic associations. In addition, a meta-analysis of previously published studies was performed to evaluate the overall association of these polymorphisms with cancer risk.</p> Results <p>The PPAR-γ rs1801282 C&gt;G variant showed a significant association with NSCLC risk in both the dominant (adjusted OR = 6.74, <i>p</i> &lt; 0.001) and allelic models (adjusted OR = 6.10, <i>p</i> = 0.001). Stratified analysis indicated higher susceptibility among males, older individuals, and nonsmokers. No significant association was observed for the MTRR rs162036 variant (<i>p</i> &gt; 0.05). The meta-analysis findings were consistent with the overall lack of association between MTRR rs162036 and cancer risk, while supporting a potential role for PPAR-γ rs1801282 in cancer susceptibility.</p> Conclusions <p>The PPAR-γ rs1801282 polymorphism may serve as a potential genetic marker for NSCLC risk in Egyptians, whereas MTRR rs162036 shows no significant impact. The combined evidence from the case–control study and meta-analysis highlights the importance of population-specific genetic investigations in NSCLC.</p>