Hepatocellular carcinoma (HCC), a common malignancy worldwide, still lacks effective clinical treatment. The study aimed to investigate the oncogenes that affect the progression of HCC and their possible mechanisms. In our study, we initially confirmed a higher level of PRDX2 in the bile of HCC patients compared to those with choledocholithiasis by 2-DE, LC-MS, and ELISA. Subsequently, we demonstrated the high expression of peroxiredoxin 2 (PRDX2) in HCC based on the TCGA database and clinical sample analysis. Furthermore, PRDX2 overexpression enhanced the viability of HCC cells. And PRDX2 silencing induced senescence of HCC cells. In vivo, knockdown of PRDX2 significantly reduced the weight of xenograft tumors. PRDX2 also was found to activate the Wnt/beta-catenin pathway by inducing beta-catenin nuclear translocation. Consequently, we proved that silencing PRDX2 could inhibit proliferation and Wnt/beta-catenin pathway while promoting senescence in HCC cells.