Background Exposure to uranium can result in multi-organ toxicity in humans. Some experimental studies have shown that uranium presents a damaging effect on liver, but no relevant population studies have been reported. Objective To investigate a potential association of plasma uranium exposure with liver injury. Methods The inhabitants of two representative areas of heavy metal pollution in northern and southern Hunan were selected as the research subjects. A total of 740 participants were recruited through 1∶1 paired case-control design based on a pre-determined diagnostic criterion for liver injury (defined as two or more anomalies among alanine aminotransferase, aspartate aminotransferase, and total bilirubin in the health examination) and the principle of case-control comparability. Information such as general demographic characteristics and medical history were collected through questionnaires and physical examination. Plasma uranium and liver function were determined by laboratory tests. Spearman correlation was applied to assess the association between plasma uranium concentration and liver injury indexes, and restricted cubic spline model was used to evaluate the dose-response relationship between plasma uranium concentration and liver injury. The participants were divided into four groups from Q1 to Q4 according to the quartile values of plasma uranium concentration of the control group after natural logarithmic transformation (with the Q1 group as the reference group), and the association between plasma uranium concentration and liver injury was evaluated by conditional logistic regression. Results The plasma uranium level in M (P₂₅, P₇₅) of the case group was 10.89 (6.78-18.53) ng·L⁻¹, higher than that in the control group, 9.26 (5.01-14.38) ng·L⁻¹ (P<0.001). The results of Spearman correlation analysis showed that alanine aminotransferase and aspartate aminotransferase were positively correlated with plasma uranium level (r_s=0.138, r_s=0.167; P<0.001). The restricted cubic spline model showed that the risk of liver injury increased with the increase of plasma uranium concentration (overall effect P<0.001). After adjusting for confounding factors such as gender, age, smoking, alcohol consumption, and prevalence of hypertension and hyperlipidemia, the results of conditional logistic regression analysis showed that the risks of liver injury in the Q2 group, the Q3 group, and the Q4 group were 2.043 (95%CI: 1.135-3.680), 2.246 (95%CI: 1.238-4.075), and 3.536 (95%CI: 1.955-6.397) times higher than that of the Q1 group respectively. Conclusion Plasma uranium exposure is associated with liver injury. This study is the first to provide population-level evidence of such an association.