This study aimed to investigate the role of uric acid (UA) in diabetic nephropathy (DN) from epidemiological and genetic perspectives.We used data from the 2007-2016 National Health and Nutrition Examination Survey to evaluate the relationship between UA and DN risk using weighted multivariate-adjusted logistic regression. Subsequently, a two-sample Mendelian randomization study was conducted using genome-wide association study summary statistics. The main inverse variance weighting (IVW) method and supplementary MR method were used to verify the causal relationship between UA and DN, and sensitivity analysis was conducted to confirm the credibility of the results.Our observational study enrolled 4363 participants with diabetes mellitus from NHANES, among them, 2682 (61.4%) participants were identified as DN. The multivariate logistic regression model showed that compared with those without hyperuricemia, the DN risk of the hyperuricemia population was significantly increased (P < 0.05). The MR results suggest a direct causal effect of hyperuricemia on DN (IVW odds ratio (OR): 1.37 (95% confidence interval 1.07-1.76); P = 0.01), which is consistent with findings from other MR methods.The evidence from observational studies indicates a positive correlation between HUA and the onset of DN. And the causal effects of HUA on DN were supported by the MR analysis.© 2024. The Author(s).