Systemic Immune Inflammatory Index (SII) is a novel indicator of inflammation. However, no studies have reported the effect of SII on the association between metals and total fat (TOFAT). We aim to investigate the mediated effect of SII on the relationship between urinary metals and TOFAT in a US adult population. This cross-sectional study was conducted among adults with complete information on SII, urine metal concentrations, and TOFAT from the 2011–2018 National Health and Nutrition Examination Survey (NHANES). Multifactorial logistic regression and restricted cubic splines were used to explore the association between urine metal levels and TOFAT. Furthermore, serial mediation analyses were used to investigate the mediating effect of SII on metals and TOFAT. A total of 3324 subjects were included in this study. After adjusting for confounders, arsenic (As), cadmium (Cd), cobalt (Co), cesium (Cs), inorganic mercury (Hg), molybdenum (Mo), manganese (Mn), lead (Pb), antimony (Sb), and thallium(Tl) had negative decreased trends of odds ratios for TOFAT (all P for trend < 0.05). In the total population, we found that Cd, Co, and Tu were positively associated with SII (β = 29.70, 79.37, and 31.08), whereas As and Hg had a negative association with SII. The mediation analysis showed that SII mediated the association of Co with TOFAT, with the β of the mediating effect being 0.9% (95%CI: 0.3%, 1.6%). Our findings suggested that exposure to As, Cd, and Hg would directly decrease the level of TOFAT. However, Co would increase TOFAT, completely mediated by SII, mainly exerted in females rather than males.