The present study was performed to investigate the protective effects of tannic acid (TA) on liver injury induced by arsenic trioxide (ATO) and to elucidate the mechanism involved as related to the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway. Adult rats were intraperitoneally injected with TA, while ATO was administered 1 h later. On the 11th day, the rats were euthanized to determine any liver histological changes, liver function, and the activities of antioxidant, antiapoptosis and proinflammatory cytokines in the liver. Furthermore, the protein expression levels of nuclear Nrf2, total Nrf2, Keap1, Heme oxygenase-1 (HO-1), NADPH quinine oxidoreductase-1 (NQO1), and gamma-glutamylcysteine synthetase (gamma-GCS) were determined using western blot analysis. The results showed that TA treatment ameliorated ATO-induced liver histological changes and decreased the ATO-induced increased alanine aminotransferase (ALT) and aspartate transaminase (AST) serum levels. Activities of the antioxidant enzymes significantly were increased, while the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) were attenuated following TA treatment. In addition, TA treatment inhibited ATO-induced liver apoptosis and inflammatory responses, increased Bcl-2 protein expression level and reduced the levels of Bax, caspase-3, interleukin (IL)-1 beta, IL-6 and tumor necrosis factor (TNF)-alpha. Furthermore, TA treatment increased the protein expression levels of Nrf2 and Keap1, HO-1, NQO1 and gamma-GCS. The results demonstrated that TA has a protective effect on ATO-treated hepatic toxicity and that its underlying mechanism could be due to TA activation of the Keap1-Nrf2/ARE signaling pathway, to reduce oxidative stress, apoptosis and inflammation in ATO-intoxicated rats.