BACKGROUND: Chronic sleep deprivation is widespread and associated with detrimental health outcomes, including inflammation. A common strategy to address weekday sleep deficits is weekend catch-up sleep (WCS). However, the relevance of the WCS on systemic inflammation, as quantified by the systemic immune-inflammation index (SII), remains inadequately understood. METHODS: This cross-sectional analysis examined data from the National Health and Nutrition Examination Survey (NHANES) 2017-2020 cohort. To explore the relationship between the WCS and the SII, we employed univariate analysis, weighted linear regression, restricted cubic spline (RCS) techniques, and subgroup analyses. RESULTS: The final sample included 4849 adults. Weighted linear regression confirmed a negative association between the WCS and the SII after adjusting for potential confounders (β = -16.72, 95 % CI: -34.29 to 0.85, P = 0.04). Subgroup analyses revealed that this association varied by obesity, gender, and age. Additionally, the association between the WCS duration and the SII was non-linear (P = 0.006) in adults with a weekday sleep duration of 7-8 h. CONCLUSION: WCS can help mitigate the inflammatory burden associated with chronic sleep deprivation. WCS durations of 3 h and longer are particularly beneficial for adults who experience sleep deprivation on weekdays. The association between WCS and SII appears to be moderated by factors such as obesity, gender, and smoking status.