A novel indicator of inflammation is the systemic immune-inflammation index (SII), and liver dysfunction is linked to the advancement of inflammation. In light of this, this study aims to look into any potential connections between SII and markers of liver injury. A cross-sectional study was conducted using the National Health and Nutrition Examination (NHANES) dataset for 2017-2020. The linear relationship between SII and markers of liver injury was examined using multiple linear regression models. Examining threshold effects and fitted smoothed curves were utilized to describe nonlinear connections. A total of 8213 adults aged 18-80 years participated in this population-based study. In the fully adjusted model, SII maintained a negative association with ALT(β = -0.003, 95%CI:-0.005, -0.002, P<0.00001), AST(β = -0.004, 95% CI:-0.005, -0.002, P<0.00001), and GGT(β = -0.004, 95% CI:-0.007, -0.000, P = 0.03791) and a positive association with ALP (β = 0.005, 95% CI:0.003, 0.007, P<0.00001). In subgroup analyses, it was found that SII remained negatively correlated with ALT, AST and GGT in gender, age and body mass index. SII was positively correlated with ALP at BMI≥25(kg/m2)(β = 0.005, 95% CI:0.003, 0.008, P = 0.00001), and was negatively correlated with ALT(β = -0.004, 95% CI:-0.005, -0.002, P<0.00001), AST(β = -0.004, 95% CI:-0.005, -0.003, P<0.00001) and GGT(β = -0.004, 95% CI:-0.008, -0.000, P = 0.02703) at BMI≥25, whereas no significant correlation was observed at BMI<25 (all P-values>0.05). Furthermore, the association between SII and markers of liver injury was nonlinear. By using a two-stage linear regression model for analysis, a U-shaped relationship was found to exist between SII and ALT with a turning point of 818.40(1,000 cells/μl). The inflection points of SII with AST and GGT were 451.20 (1,000 cells/μl) and 443.33 (1,000 cells/μl), respectively, and no significant inflection point with ALP was observed. Interaction tests demonstrated that SII correlation with ALT, AST, ALP, and GGT was not significantly different between strata (all p for interaction>0.05). The research findings suggested that there was a negative correlation between SII and ALT, AST and GGT, and a positive correlation with ALP. However, larger prospective investigations are still greatly needed to confirm the findings.