Background <p>The relationship between estimated glucose disposal rate (eGDR), systemic inflammation response index (SIRI), and mortality in patients with dyslipidemia remains inconclusive. This study aimed to evaluate the independent and joint associations of eGDR and SIRI with all-cause and cardiovascular mortality.</p> Methods and results <p>This study included a total of 12,854 dyslipidemia patients from the National Health and Nutrition Examination Survey (1999–2018). Kaplan-Meier (KM) survival curves and weighted Cox regression analyses were performed to assess differences in mortality risk among different groups. Time-dependent ROC curves were used to assess predictive accuracy. The optimal cut-off values identified by maximally selected rank statistics method (MSRSM) were 7.84 for eGDR and 1.54 for SIRI. In the adjusted Cox regression model, lower eGDR (&lt; 7.84) and higher SIRI (&gt; 1.54) were independently associated with increased all-cause (eGDR, HR = 1.27, 95% CI 1.06–1.52; SIRI, HR = 1.48, 95% CI 1.32–1.65) and cardiovascular mortality (eGDR, HR = 1.54, 95% CI 1.08–2.19; SIRI, HR = 1.83, 95% CI 1.38–2.42). The joint analysis of eGDR and SIRI indicated that, compared to participants with eGDR ≥ 7.84 and SIRI ≤ 1.54, those with eGDR &lt; 7.84 and SIRI &gt; 1.54 had the highest risk of all-cause mortality (HR = 1.81, 95% CI: 1.45–2.25) and cardiovascular mortality (HR = 2.45, 95% CI: 1.56–3.83). Time-dependent ROC results showed that the combination of eGDR and SIRI had superior predictive performance for all-cause and cardiovascular mortality.</p> Conclusions <p>Our study demonstrated that eGDR and SIRI were closely associated with mortality risk in patients with dyslipidemia. In addition, the combination of eGDR and SIRI showed a better ability to identify individuals at high risk of mortality.</p> Graphical abstract <p></p>