The anti-fibrotic mechanism of combination therapy with taurine, epigallocatechin gallate and genistein was studied from the perspective of serum proteomics in our previous work. In order to further investigate and systematically analyse other possible therapeutic mechanism of combination therapy against liver fibrosis, isobaric tags for relative and absolute quantification (iTRAQ) proteomic analysis was applied to study the protein profile changes in liver tissue of carbon tetrachloride-induced liver fibrosis rats after combination therapy. A total of 115 differentially expressed proteins containing 84 up-regulated and 31 down-regulated proteins in response to combination therapy were identified. Three differentially expressed proteins (Txn1, Ctsd and Cdk4) involved in antioxidant defense system and the activation and proliferation of hepatic stellate cell were selected for further validation by western blot and real-time PCR analysis. Our study highlight the importance of differentially expressed proteins Txn1, Ctsd and Cdk4 against liver fibrosis, which may provide a more precise and comprehensive perspective for clarifying the roles of combination therapy as a potential agent for treatment of liver fibrosis.