Background <p>Estimated glucose disposal rate (eGDR) is a novel insulin resistance (IR) assessment surrogate. Although it has shown promising potential in other metabolic disease studies, no research has yet explored its relationship with osteoarthritis (OA). Therefore, this study aims to investigate the association between eGDR and OA in a cross-sectional observational cohort.</p> Method <p>Data utilized in this cross-sectional study were drawn from the National Health and Nutrition Examination Survey (NHANES). Logistic regression models were used to evaluate the association between eGDR and OA, stratified analysis was applied to assess the stability of the results.</p> Result <p>A total of 19,040 participants were included in the study, including 2,001 OA patients and 17,039 non-OA participants with an age distribution ranging from 20 to 85 years. The fully adjusted logistic regression model shows that eGDR were less likely associated with OA compared to those with non-OA (OR = 0.879, 95% CI = 0.846–0.914, <i>P</i> &lt; 0.001). By dispersing the eGDR into quartiles, the correlation between eGDR and OA remained significant (<i>P</i> for trend &lt; 0.0001).</p> Conclusion <p>This study suggests that eGDR is independently associated with OA, with lower eGDR values being linked to a higher risk of OA.</p> Clinical trial number <p>Not applicable.</p>