Purpose <p>Overweight/obesity is a critical global health crisis associated with cardiovascular disease (CVD) and mortality. Insulin resistance (IR) is a key pathophysiological mediator, but non-invasive IR markers for large-scale studies are limited. While the estimated glucose disposal rate (eGDR) predicts CVD outcomes in diabetes, its role in overweight/obese adults remains unexplored. This study aimed to, first, investigate the cross-sectional association between eGDR-a validated surrogate of insulin resistance calculated from waist circumference, hypertension status, and glycated hemoglobin (HbA1c)-and the prevalence of CVD, and second, to examine the prospective association between eGDR and the risk of all-cause and CVD-specific mortality among adults with overweight/obesity.</p> Methods <p>Using 1999–2020 NHANES data, we conducted a cross-sectional study (<i>N</i> = 17,671) assessing eGDR-CVD relationships via logistic regression. A cohort study (<i>N</i> = 14,946; mean follow-up 9.8 years) evaluated eGDR-mortality associations using Cox regression, Kaplan-Meier analysis, and restricted cubic splines. Sensitivity analyses and ROC curves compared eGDR’s predictive utility against HOMA-IR.</p> Results <p>In cross-sectional analyses, lower eGDR correlated with higher CVD risk. Cohort analyses revealed inverse relationships between eGDR and all-cause mortality [Q4 vs. Q1: HR = 0.72 (0.56–0.94), <i>P</i> = 0.01] and CVD mortality [Q4 vs. Q1: HR = 0.48 (0.27–0.84), <i>P</i> = 0.01]. ROC curves demonstrated eGDR’s superior mortality prediction over HOMA-IR. Results remained robust in sensitivity analyses, with stronger prognostic value than insulin resistance measures.</p> Conclusion <p>Low levels of eGDR were related with the risk of CVD and mortality in adults with overweight/obesity.</p>