This study investigates the association between systemic immune-inflammatory index (SII) and diabetes mellitus (DM) in a large sample of participants from the National Health and Nutrition Examination Survey (NHANES) 2005-2018. The study also examines the mediating role of obesity indicators (BMI, waist circumference, visceral adiposity index, and lipid accumulation product index) in this relationship. Key findings include: 1. **Association Between SII and DM**: SII levels were significantly higher in individuals with DM compared to those without DM, and SII demonstrated a positive correlation with the risk of DM, with a significant dose-response relationship observed across all models (p-trend <0.05). 2. **Mediating Role of Obesity Indicators**: BMI and waist circumference (WC) mediated the relationship between SII and DM, with respective mediation proportions of 9.34% and 12.14% for SII, and 10.23% and 13.67% for natural logarithm (Ln)-SII. This suggests that obesity indicators play a crucial role in the link between inflammation and DM. 3. **Sensitivity Analyses**: Sensitivity analyses redividing SII into tertiles yielded similar results, confirming the robustness of the findings. 4. **Discussion**: The study highlights the complex interplay between inflammation and obesity in the development of DM. Management of systemic inflammation and weight loss may be effective strategies to prevent DM. 5. **Conclusion**: Elevated SII levels are independently associated with an increased risk of DM, with BMI and WC acting as significant mediators in this relationship. Proper control of obesity can help reduce the effects of inflammation on DM. The study's strengths include its large sample size, use of diverse obesity indicators, and comprehensive adjustment for confounding variables. However, the observational nature of the study limits the establishment of causal relationships, and the findings may not be generalizable to all populations.This study investigates the association between systemic immune-inflammatory index (SII) and diabetes mellitus (DM) in a large sample of participants from the National Health and Nutrition Examination Survey (NHANES) 2005-2018. The study also examines the mediating role of obesity indicators (BMI, waist circumference, visceral adiposity index, and lipid accumulation product index) in this relationship. Key findings include: 1. **Association Between SII and DM**: SII levels were significantly higher in individuals with DM compared to those without DM, and SII demonstrated a positive correlation with the risk of DM, with a significant dose-response relationship observed across all models (p-trend <0.05). 2. **Mediating Role of Obesity Indicators**: BMI and waist circumference (WC) mediated the relationship between SII and DM, with respective mediation proportions of 9.34% and 12.14% for SII, and 10.23% and 13.67% for natural logarithm (Ln)-SII. This suggests that obesity indicators play a crucial role in the link between inflammation and DM. 3. **Sensitivity Analyses**: Sensitivity analyses redividing SII into tertiles yielded similar results, confirming the robustness of the findings. 4. **Discussion**: The study highlights the complex interplay between inflammation and obesity in the development of DM. Management of systemic inflammation and weight loss may be effective strategies to prevent DM. 5. **Conclusion**: Elevated SII levels are independently associated with an increased risk of DM, with BMI and WC acting as significant mediators in this relationship. Proper control of obesity can help reduce the effects of inflammation on DM. The study's strengths include its large sample size, use of diverse obesity indicators, and comprehensive adjustment for confounding variables. However, the observational nature of the study limits the establishment of causal relationships, and the findings may not be generalizable to all populations.