BACKGROUND: While there is some evidence of the association between sedentary behavior and sarcopenia risk, it remains unclear whether systematic inflammation index (SII), 25(OH)D, and testosterone can mediate this association. This study aims to investigate whether sedentary behavior is associated with the prevalence of sarcopenia in the US population and further examine its potential mediators which have not been thoroughly explored, thereby presenting a novel approach to understanding the mechanism between sedentary behavior and sarcopenia. METHODS: We conducted a cross-sectional study involving a representative sample of the US national population of 9902 adults aged 18 years or older from the National Health and Nutrition Examination Survey (NHANES) 2011-2018. The participants with sarcopenia were identified by Dual-energy X-ray (DXA) absorptiometry. Weighted multivariable logistic regressions based on the complex survey designs were used to explore the associations between a sedentary lifestyle and the risk of sarcopenia and restricted cubic spline (RCS) regression was used to examine the non-linear association. Causal mediation analysis using the quasi-Bayesian Monte Carlo method was applied to identify the mediating role of SII, 25(OH)D, and testosterone as potential mediators. RESULTS: A total of 358 participants (3.6 %) had sarcopenia. Compared to those in the lowest quartile of sedentary time, participants in the highest quartile had a hazard ratio of 1.631 (95 % CI: 1.162 to 2.289) for the prevalence of sarcopenia. A non-linear relationship (P for non-linearity <
0.001) between sedentary time and the risk of sarcopenia was observed using the RCS method. The odds ratio for sarcopenia was highest (OR = 3.427) when the sedentary time was 1080 min daily. Furthermore, SII, 25(OH)D, and testosterone showed a significant mediation in the association between sedentary time and sarcopenia risk, with a mediation effect of 3.39 %, 10.3 %, and 8.56 %, respectively. CONCLUSIONS: This study demonstrated novel findings of the association between sedentary behavior and sarcopenia in the US population. Our study found that sedentary time was associated with the prevalence of sarcopenia. Vitamin D, SII, and testosterone served as mediating factors in the association of sedentary time with the risk of sarcopenia.