Doxorubicin (DOX), which is frequently used in cancer treatment, has limited clinical use due to adverse effects on healthy tissues, especially the liver. Therefore, it is necessary to research the molecular basis of DOX‐induced organ and tissue damage and protective agents. In this study, we aimed to examine the protective effects of tannic acid (TA) against DOX‐induced hepatoxicity in experimental rat models. Rats were randomly divided into four experimental groups: the untreated control, DOX, TA, and cotreatment (DOX + TA) groups. We investigated the antioxidant system's main components and oxidative stress indicators. Moreover, we examined alterations in the mRNA expression of critical regulators that modulate apoptosis, inflammation, and cell metabolism to better understand the underlying factors of DOX‐induced liver toxicity. The results showed that DOX exposure caused an increase in MDA levels and a significant depletion of GSH content in rat liver tissues. Consistent with oxidative stress‐related metabolites, DOX was found to significantly suppress both mRNA expression and enzyme activities of antioxidant system components. Moreover, DOX exposure had significant adverse effects on regulating the other regulatory genes studied. However, it was determined that TA could alleviate many of the negative changes caused by DOX. The results of the present study indicated that TA might be considered a versatile candidate that could prevent DOX‐induced hepatotoxicity, possibly by preserving cell physiology, viability, and especially redox balance.