Background: Diabetic nephropathy (DN) is a severe microvascular complication of diabetes and a leading cause of end-stage renal disease. Inflammation, insulin resistance, and oxidative stress are key drivers of DN progression. The C-reactive protein-triglyceride-glucose index (CTI), which integrates inflammatory and metabolic signals, has shown prognostic value in multiple diseases, but its association with DN remains unclear. We aimed to explore the relationship between CTI and DN and the mediating role of oxidative stress. Methods: Based on 7 cycles (2001-2010, 2015-2018) of NHANES, 2213 diabetic patients were included after excluding those with missing key data. Weighted logistic regression, restricted cubic spline, subgroup analysis, and Bootstrap mediation analysis were employed to evaluate the association between CTI and DN, non-linear relationships, stability, and the mediating effects of gamma-glutamyl transferase (GGT) and uric acid (UA). Results: The DN prevalence was 43.11% in diabetes. CTI was independently and non-linearly associated with DN (OR = 1.49, P < 0.001), with a stronger association in the highest quartile (OR = 2.74, P < 0.001). Subgroup analysis confirmed stable associations across most populations. GGT and UA partially mediated the association, with mediation proportions of 6.95% and 9.70%, respectively. Conclusion: CTI is significantly associated with increased DN risk in diabetic patients, with oxidative stress partially mediating this relationship. As an accessible composite biomarker, CTI may serve as a practical tool for DN risk stratification, underscoring the clinical importance of targeting inflammation, metabolic dysfunction, and oxidative stress in the prevention of DN.