Background <p>Moderate consumption of polyunsaturated fatty acids has been shown to confer a protective effect against proteinuria and to slow the progression of chronic kidney disease.</p> Objective <p>This study aimed to systematically examine the relationship between polyunsaturated fatty acid intake and proteinuria in the U.S. population, with the goal of providing a foundation for dietary interventions in patients with kidney disease.</p> Methds <p>This study utilized data from the National Health and Nutrition Examination Survey (NHANES) conducted between 2009 and 2012 and 2015–2018. Various statistical methods, including descriptive analysis, multivariate logistic regression, the XGBoost machine learning model, and receiver operating characteristic (ROC) curves, were employed to evaluate the relationship between polyunsaturated fatty acid intake and the risk of proteinuria.</p> Results <p>An analysis of the NHANES database, after controlling for various variables such as demographic characteristics and lifestyle factors, revealed that polyunsaturated fatty acid intake was significantly associated with the risk of proteinuria (OR = 0.99; 95% CI: 0.98–0.99; <i>p</i> &lt; 0.001). These findings suggest that moderate intake of polyunsaturated fatty acids may have a protective effect against proteinuria.</p> Conclusion <p>The results of this study, derived from a comprehensive analysis of NHANES data, suggest that moderate intake of polyunsaturated fatty acids may help delay the progression of renal disease and could serve as a potential dietary intervention strategy for patients with renal disease.</p>