The present study aimed to describe the expression and purification of cyclophilin-type peptidylprolyl cis-trans isomerase (PPI) from the red alga Pyropia yezoensis. The antioxidant activity of the purified protein was also demonstrated, based on its ability to act against oxidative stress in HepG2 human hepatocellular carcinoma cells. HepG2 cells that were treated with recombinant PPI protein exhibited a reduction in the formation of hydrogen peroxide (H2O2)‑mediated reactive oxygen species (ROS). In HepG2 cells, treatment of recombinant PPI protein expression diminished H2O2‑mediated oxidative stress and restored both the expression and the activity of certain antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and thioredoxin reductase (TRR). CAT, SOD and TRR activities were upregulated by treatment with the purified protein. CAT mRNA expression was significantly increased in HepG2 cells treated with recombinant PPI protein. These enzymes are the first line of antioxidant defense against ROS generated in times of oxidative stress. Accordingly, data from the present study indicate that the recombinant PPI protein is able to regulate the expression of antioxidant enzymes. Recombinant PPI has antioxidant properties that prevent oxidative stress‑induced toxicity, enhance cell viability, decrease ROS production and inhibit oxidative damage and mitochondrial dysfunction in HepG2 cells. Therefore, the present study hypothesizes that the recombinant PPI protein has the potential to protect the liver against oxidative stress‑induced cell damage and should be considered as an antioxidant.