Objective <p>To investigate the association between Endothelial Activation and Stress Index (EASIX) and diabetic retinopathy (DR) among patients with diabetic kidney disease (DKD).</p> Methods <p>A cross-sectional study was conducted based on the National Health and Nutrition Examination Survey (NHANES) database. Participants were divided into quartiles according to EASIX scores. Survey-weighted generalized linear models (SWGLMs) were used to evaluate the association between EASIX and DR, with restricted cubic spline (RCS) analysis to examine non-linear relationships. Stratified analyses were performed by gender, race, age, Body Mass Index (BMI), smoking status, alcohol consumption, blood pressure, and renal function.</p> Results <p>After multivariate adjustment, each unit increase in EASIX was associated with a 32% higher risk of DR (OR: 1.32, 95% CI: 1.04–1.69, <i>P</i> = 0.024). In quartile analysis, compared with the first quartile, the fourth quartile showed a trend toward increased DR risk (OR: 1.60, 95% CI: 0.99–2.59, <i>P</i> = 0.054), with a significant dose-response trend (P for trend = 0.040). RCS analysis revealed a significant overall association between EASIX and DR (P for overall &lt; 0.001), while the non-linear association was not significant (P for nonlinear = 0.075). Stratified analyses demonstrated that this association remained consistent across different population characteristics.</p> Conclusion <p>EASIX is significantly associated with DR in DKD patients and may serve as a potential marker for DR risk assessment.</p>