Objective The relationship between non-high-density lipoprotein (NHDL) cholesterol to high-density lipoprotein cholesterol (HDL-C) ratio (NHHR) and stoke remains unknown. This study aimed to evaluate the association between the adult NHHR and stroke occurrence in the United States of America (USA). Methods To clarify the relationship between the NHHR and stroke risk, this study used a multivariable logistic regression model and a restricted cubic spline (RCS) model to investigate the association between the NHHR and stroke, and data from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2018. Subgroup and sensitivity analyses were conducted to test the robustness of the results. Results This study included 29,928 adult participants, of which 1,165 participants had a history of stroke. Logistic regression analysis of variables demonstrated a positive association between NHHR and stroke (OR 1.24, 95% CI: 1.03-1.50, P = 0.026). Compared with the lowest reference group of NHHR, participants in the second, third, and fourth quartile had a significantly increased risk of stroke after full adjustments (OR: 1.35, 95% CI: 1.08-1.69) (OR: 1.83, 95% CI: 1.42-2.36) (OR: 2.04, 95% CI: 1.50-2.79). In the total population, a nonlinear dose-response relationship was observed between the NHHR and stroke risk (P non-linearity = 0.002). This association remained significant in several subgroup analyses. Further investigation of the NHHR may enhance our understanding of stroke prevention and treatment. Conclusion Our findings suggest a positive correlation between the NHHR and an increased prevalence of stroke, potentially serving as a novel predictive factor for stroke. Timely intervention and management of the NHHR may effectively mitigate stroke occurrence. Prospective studies are required to validate this association and further explore the underlying biological mechanisms.