The systemic immune-inflammation index (SII) is an emerging inflammatory marker. Carotenoids have anti-inflammatory properties. Therefore, this study aims to explore the association of serum carotenoids with SII. This cross-sectional study analyzed data from the 2001 to 2006 and 2017 to 2018 cycles of National Health and Nutrition Examination Survey. Multivariate linear regression models were employed to evaluate the relationship. Restricted cubic splines models were used to assess potential nonlinear relationships. Subgroup analyses and sensitivity analysis were also performed. Our study included 11,914 eligible participants. After adjusting for all covariates, the total carotenoids levels showed a negative correlation with SII (P < .001). Furthermore, the levels of α-carotene, β-carotene, β-cryptoxanthin, and lutein/zeaxanthin still had significant negative associations (all P < .001). Specifically, individuals in the highest quartile of α-carotene, β-carotene, β-cryptoxanthin, lutein/zeaxanthin, and lycopene had lower SII levels compared to those in the lowest quartile (all P < .05). Nonlinear relationships were observed between total carotenoids, α-carotene, β-carotene, β-cryptoxanthin, lutein/zeaxanthin, and SII (all P < .05), while a linear relationship between lycopene and SII was found (P = .070). Subgroup analyses and sensitivity analysis indicated that the results were robust. This study reveals a significant negative association between serum carotenoids and SII, highlighting the potential anti-inflammatory role of carotenoids.