Blood urea nitrogen (BUN) level is one of the commonly used indicators to assess renal function and systemic immune-inflammatory status. In the adolescent population, changes in BUN levels may be associated with a variety of factors, including physiologic dehydration, lifestyle influences such as nutritional intake, physical activity, and possible endocrine or metabolic disorders. In recent years, more and more studies have shown that BUN levels are not only a reflection of kidney function, but it may also be related to the inflammatory state of the body. The Systemic Immune Inflammatory Index (SII) is a comprehensive index that takes into account platelet counts, neutrophil and lymphocyte counts, and is thought to be effective in reflecting the body's immune status and inflammatory response. However, research on the relationship between the two, SII and BUN, remains understudied in the adolescent population. The purpose of this study was to examine the relationship between SII and BUN levels in a population of American adolescents and to further analyze the factors that influence it. We conducted a cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES) database. Using descriptive statistics, correlation analysis, and regression analysis, we explored the relationship between SII and BUN levels. We found a significant negative correlation between SII and BUN levels, with BUN levels decreasing when SII levels increased (BUN as the dependent variable and SII as the outcome variable). We performed a multiple regression analysis of this relationship, controlling for possible confounders such as gender, age, race, and BMI, and found that this negative correlation remained significant. Our findings reveal an important relationship between SII and BUN levels and provide new perspectives for understanding adolescent health.