Animal feed may contain different phenolic antioxidants, such as butylated hydroxyanisole, butylated hydroxy toluene (BHT), and ethoxyquin (EQ). EQ and BHT at high concentrations can have a pro-oxidant effect and can cause adverse health effects in animals. This study was designed to evaluate the hepatotoxic effect of EQ and / or BHT in rats. Fifty male Sprague–Dawley rats were assigned to five groups of 10 rats each as following: the first group served as control and did not receive any treatments; the second group served as vehicle control and was orally given corn oil. The third group was orally administered EQ day after day in a dose of 1/5 of LD50, the fourth group was orally received BHT day after day in a dose of 1/5  LD50. The fifth group was orally administered both EQ and BHT at the same doses and durations described above. The duration of this study was 45 and 90 days. The results revealed that EQ, BHT and their co-exposure caused a significant decrease in levels of antioxidant enzymes (superoxide dismutase (SOD), catalase enzyme (CAT) and reduced glutathione (GSH)) in rats. Also a significant increase in malondialdehyde (MDA) and 8-hydroxyguanosine (8-OH-dG) levels was recorded in serum of rats. Co-exposure group had a significant increase in DNA damage variables (% tail DNA, tail length, and Olive Tail Moment (OTM)), strong immuno positive reactivity of caspase3 and up regulation of CYP1A1 gene expression in the liver cells of exposed rats. In conclusion, we can state that EQ and BHT are potentially hepatotoxic compounds where the oxidative stress could be accepted as a possible mechanism of their toxicity. Therefore, the utilization of such compounds as feed additives should be more controlled and limited.