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BackgroundThere is limited research on the relationship between Systemic Oxidative Stress (SOS) status and inflammatory indices. Adding onto existing literature, this study aimed to examine the association between dietary Oxidative Balance Score (OBS) and lifestyle OBS (which make up the overall OBS), and Cardiovascular Disease (CVD) prevalence at different Systemic Immune Inflammation Index (SII) and Systemic Inflammatory Response Index (SIRI) levels.MethodsThis study involved 9,451 subjects selected from the National Health and Nutrition Examination Survey (NHANES) 2007–2018. The OBS comprised 20 dietary and lifestyle factors. Statistical methods included Weighted Linear Regression Analysis (WLRA), Logistic Regression Analysis (LRA), Sensitivity Analysis (SA), and Restricted Cubic Spline (RCS) analysis.ResultsThe multivariate WLRA revealed that OBS was significantly negatively correlated with both SII (β = −5.36, p < 0.001) and SIRI (β = −0.013, p < 0.001) levels. In SA, removing any single OBS component had no significant effect on the WLRA results of SII and SIRI. Further subgroup analyses revealed that OBS was more impactful in lowering SII in women than in men. Additionally, OBS was more significantly negatively correlated with SII and SIRI in the low-age group than in the high-age group. Moreover, RCS analysis confirmed this linear relationship. Compared to dietary OBS, lifestyle OBS exerted a more significant effect on Coronary Artery Disease (CAD) (OR: 0.794, p = 0.002), hypertension (OR: 0.738, p