Background <p>Type 2 diabetes mellitus (T2DM) is a multifactorial disease influenced by genetic and environmental factors.</p> Objective <p>This systematic review and meta-analysis aimed to synthesize available evidence on the association between the PON1 gene polymorphism and susceptibility to T2DM.</p> Methods <p>A comprehensive literature search on PubMed, Web of Science, and Google Scholar was conducted for studies published between 2014 and 2025. Eligible case–control, cohort, and cross-sectional studies reporting genotype distributions of the PON1 gene polymorphism in T2DM patients and controls were included, and quality assessment was performed using the Newcastle–Ottawa Scale (NOS) and Q-Genie tool. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using random-effects models for dominant (QR + RR vs QQ), recessive (RR vs QQ + QR), codominant (QR vs QQ; RR vs QQ), and allelic (R vs Q) models. Heterogeneity was quantified using <i>I</i>² statistics, sensitivity analyses included Hardy–Weinberg equilibrium testing, and publication bias was evaluated with funnel plots and Egger’s regression test. Certainty of evidence was graded using the GRADE framework.</p> Results <p>Fifteen eligible studies comprising 1614 T2DM cases and 1598 controls were included. The PON1 Q192R polymorphism was associated with increased T2DM susceptibility in the dominant model (OR = 1.58; 95% CI: 1.35–1.85), with supportive associations observed in the recessive (OR = 1.49; 95% CI: 1.20–1.87), codominant QR vs QQ (OR = 1.45; 95% CI: 1.30–1.62), codominant RR vs QQ (OR = 1.88; 95% CI: 1.44–2.47), and allelic models (OR = 1.40; 95% CI: 1.21–1.62). Descriptive subgroup analyses showed numerically different estimates across regions and genotyping methods, but these findings were exploratory, underpowered, and not supported by formal interaction testing. Egger’s regression did not provide strong statistical evidence of small-study effects; however, publication bias cannot be excluded. The certainty of evidence was rated as low across all models.</p> Conclusions <p>The present evidence synthesis suggests that the PON1 Q192R polymorphism may be associated with increased susceptibility to type 2 diabetes mellitus. Across multiple genetic models, carriers of the R allele demonstrated higher odds of T2DM, although these findings should be interpreted cautiously given the observational nature of the included studies. The certainty of evidence was rated as low according to the GRADE framework. Exploratory subgroup analyses suggested potential variation across populations, while evidence from several regions remains limited and inconclusive. Overall, these findings support biological plausibility but do not establish causality. Further large-scale, well-designed, multiethnic prospective studies are required to confirm these associations and evaluate their clinical relevance.</p>