AIM: To study the effect of hepatitis B combined with hepatic fibrosis on endogenous and exogenous metabolism of liver and the effect of glycyrrhizic acid combined with tenofovir (TFV) ester on anti-HBV efficacy. METHODS: Hepatitis B mouse was induced by chronic CCl4 to form a model of hepatitis B with hepatic fibrosis. H&E staining, Sirius Red Staining, α-SMA immunohistochemistry were used to detect pathological changes in liver tissue. The changes of liver endogenous metabolism in mice with hepatitis B and hepatic fibrosis were detected by metabolomics. LC-MS/MS was used to investigate the plasma and liver concentrations of TFV and its active metabolite (TFV-DP), for investigating the changes of exogenous metabolism. RESULTS: HBV+CCl4 mice showed fibrosis symptoms such as liver injury and collagen deposition. Hepatitis B combined with hepatic fibrosis affected nucleotide metabolism, amino acid metabolism, tricarboxylic acid cycle, pentose phosphate pathway and other endogenous metabolism, lowered the hepatic level of TFV-DP, and decreased the antiviral efficacy. By combining with glycyrrhizic acid or forming a self-assembled preparation, the hepatic level of TFV-DP was improved, and the antiviral efficacy was enhanced. CONCLUSIONS: Hepatitis B combined with hepatic fibrosis affected both endogenous and exogenous metabolism of liver. Different forms of combination of glycyrrhizic acid and TFV could elevate the level of TFV-DP in liver and improve the antiviral efficacy in HBV+CCl4 mice.