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Introduction: One of the complications of diabetes mellitus (DM) is diabetic nephropathy (DN), which plays a significant role in the progression of end‐stage renal disease. Oxidative stress is implicated in DN pathogenesis, and genetic variations in antioxidant enzymes such as superoxide dismutase 2 (SOD2) and catalase (CAT) may contribute to the susceptibility. This study aimed to investigate the potential association between single nucleotide polymorphisms (SNPs) in antioxidant enzymes, specifically SOD2 rs4880 and CAT rs769217, and the risk of T2D and susceptibility to DN within the Saudi population. Methods: This case–control study included 150 participants, comprising 50 patients with T2D without DN (group 1), 50 patients with T2D with DN (group 2), and 50 healthy participants (group 3). The samples were genotyped using real‐time PCR for SOD2 rs4880 and CAT rs769217 SNPs. Sanger sequencing was used for validation. Statistical analyses were performed to explore associations between these SNPs and T2D with or without DN. Results: No significant difference was observed in CAT rs769217 expression between the groups. However, a significant difference was observed in SOD2 rs4880 expression between the healthy controls and patients with T2D with DN (p =.028). Furthermore, SOD2 rs4880 was associated with approximately threefold increased risk of DN in patients with T2D compared to that in healthy participants (odds ratio [OR] = 2.99 [1.31–6.83]). Validation through Sanger sequencing further confirmed these findings. Conclusions: The findings of this study provide evidence that SOD2 rs4880 SNP may contribute to inadequate defence by the antioxidant enzyme, SOD2, against DM‐induced oxidative stress and thus cause DN in Saudi patients with T2D. Therefore, SOD2 rs4880 may serve as a predictive marker to prevent the development and progression of DN in patients with T2D. [ABSTRACT FROM AUTHOR]