Liver as iron storage organ is particularly susceptible to oxidative stress-induced injury from excess iron. Thus, antioxidant therapies are often used to reverse oxidative damage and protect cells and tissues. This study investigated the protective effects of phenolic acids; ferulic acid (FA) and its metabolite, ferulic acid 4-O-sulfate disodium salt (FAS) against oxidative stress under iron overload conditions in mouse and HepG2 cells. Cells were exposed to FA or FAS and then treated with iron-induced oxidative stress complex of 50 μmol/L FAC and 20 μmol/L of 8-hydroxyquinoline 8HQ (8HQ-FAC). Iron dextran was injected intraperitoneally on alternate days for 10 days to induce the iron overload condition in BALB/c mice. The study revealed that the phenolic acids were protective against ROS production, lipid peroxidation and antioxidant depletion in HepG2 cells and liver tissues of BALB/c mice during iron-induced oxidative stress. The protective function of phenolic acids was achieved by the transcriptional activation of nuclear factor erythroid-2-related factor 2 (Nrf2) to regulate antioxidant genes. In conclusion, the study provides evidence that FA has the potential as a therapeutic agent against iron-related diseases such as T2D.