Abstract: Epidemiological data are scarce regarding the association of exposure to mixtures of per- and polyfluoroalkyl substances (PFASs) with liver injury in the general population. In the current study, therefore, we examined data from the National Health and Nutrition Examination Survey (2009–2018). The PFAS exposure levels were defined by the serum concentrations of PFASs with over 70% detection in samples, namely perfluorooctanoic acid, perfluorononanoic acid, perfluorohexane sulfonic acid, perfluorodecanoic acid, and perfluorooctane sulfonic acid (PFOS). We evaluated liver injury from two aspects: first, the degree of liver inflammation was determined based on levels of the serum alanine aminotransferase, aspartate aminotransferase, glutamyltransferase, and total bilirubin; second, the degree of liver fibrosis was determined based on the fibrosis-4 index. We assessed the associations of individual or total PFAS exposure with these liver injury outcomes using multivariable linear and logistic regression models, restricted cubic splines, and weighted quantile sum regression. Among the samples of 7484 American adults, the median concentration of PFOS was the highest, followed by perfluorooctanoic acid and perfluorohexane sulfonic acid. Using multivariable linear regression, we observed positive correlations between all PFAS exposure and liver enzyme levels, such as alanine aminotransferase, aspartate aminotransferase, and total bilirubin. Additionally, the weighted quantile sum model indicated an overall positive association between exposure to the five PFASs and liver injury risk. For liver function biomarkers and liver fibrosis, perfluorononanoic acid and PFOS were the most heavily weighted chemicals, respectively. Our findings provide new epidemiological evidence indicating potential associations between PFAS exposure and adverse effects on liver injury biomarkers, highlighting the potentially harmful effects of PFAS exposure on human liver health.