Abstract Obesity is a prevalent health issue among adolescents, characterized by chronic low-grade inflammation, which increases the risk of developing various chronic diseases in the future. The systemic immune-inflammation index (SII) serves as an indicator of inflammation and immune response. This study conducted a cross-sectional analysis using data from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2016, including 5,676 participants. A multivariate logistic regression model, Generalized Additive Models (GAM), and subgroup analysis were used to examine the relationship between obesity and SII. The multivariate logistic regression results revealed a significant positive correlation between log SII and adolescent obesity (1.254 [1.024–1.537]). Furthermore, the risk of obesity increased with higher quartiles of SII. Subgroup analysis and interaction tests showed that this positive association persisted across various factors, including female gender, race (Non-Hispanic White and Mexican American), non-hyperlipidemia, normal white blood cell count, and PIR