Peroxiredoxin 5 (PRDX5) is the member of Prxs family, widely reported to be involved in various types of cell death. We previously found that PRDX5 knockdown increases the susceptibility of cell death upon oxidative stress treatment. Ethyl β-carboline-3-carboxylate (β-CCE), an alkaloid extracted from Picrasma quassioides, has been reported to play a role in neuronal disease, but its anti-cancer potential on liver cancers remains unknown. Here, we studied the effect of PRDX5 on ethyl β-carboline-3-carboxylate (β-CCE)-induced apoptosis of hepatomas. High expression level of PRDX5 was deeply related with the postoperative survival of patients with liver cancer, indicating that PRDX5 may be a biomarker of live cancer processing. Moreover, PRDX5 over-expression in HepG2 cells significantly inhibited β-CCE-induced cell apoptosis and cellular ROS levels as well as mitochondrial dysfunction. Signalling pathway analysis showed that β-CCE could significantly up-regulate the ROS-dependent MAPK signalling, which were in turn boosts the mitochondria-dependent cell apoptosis. Moreover, PRDX5 over-expression could reverse the anti-cancer effects induced by β-CCE in HepG2 cells. Our findings suggest that PRDX5 has a protective role on β-CCE-induced liver cancer cell death and provides new insights for using its anti-cancer properties for liver cancer treatment. © 2022 Ivyspring International Publisher. All rights reserved.