BACKGROUND: Inflammatory responses and lipid metabolism play critical roles in diabetes development. This study explored the association between the neutrophil-to-high-density lipoprotein cholesterol ratio (NHR) and diabetes prevalence and mortality. METHODS: This cross-sectional study was conducted in the National Health and Nutrition Survey (NHANES) from 1999 to 2018. The correlation between NHR and the prevalence of diabetes was evaluated using logistic regression models. Additionally, the Cox proportional hazards model was applied to investigate whether NHR related to the risk of mortality from all causes and cardiovascular diseases. A series of sensitivity analyses and subgroup analyses were performed to test the robustness of the findings. RESULTS: Among the 52,428 study participants, 8,114 (15.48%) had diabetes, with a mean neutrophil-to-high-density lipoprotein cholesterol ratio (NHR) of 3.49. In the full-adjusted model, each unit increase in NHR was related to a 17.0% higher risk of diabetes (odds ratio, 1.17 [95% CI 1.13-1.21], P < 0.001). Results were similar when participants were categorized by NHR tertiles (odds ratio, 2.08 [95% CI 1.76-2.47], comparing extreme quartiles). The stratified analyses showed that the association between NHR and risk of diabetes was more obvious in female, White, former smokers and participants with age ≥ 50 years. After a median (interquartile range) follow-up of 9.42 (5.08-14.33) years, higher NHR levels were positively associated with the risk of all-cause and cardiovascular disease mortality in diabetes patients. A series of sensitivity analyses confirmed the robustness of the findings. CONCLUSION: Elevated NHR is linked to higher diabetes prevalence and increased mortality risk in a U.S. population, independent of traditional risk factors. Regular monitoring of NHR may serve as an easy-to-measure tool for risk stratification for diabetes and its adverse outcomes. CLINICAL TRIAL NUMBER: Not applicable.