Doxorubicin (DOX) is a potent anticancer drug; its use has been limited by its hepatotoxicity, which is due to free radicals generation. Propolis, a honeybee product very rich in flavonoids and therapeutic possibilities, has gained popularity as a food and alternative medicine. The present study treats DOX pro-oxidant effect on hepatic cells and mitochondrial functions. The prophylactic effect of propolis ethanolic extract (EEP) against DOX induced mitochondrial oxidative stress has also been investigated. We find that doxorubicin at the amount of 10mg/Kg altered liver mitochondrial functions as attested by the overproduction of superoxide anion (O2(2-)) by mitochondrial respiratory chain complex III. The hepatic tissue from DOX treated rats showed also a marked depletion in reduced GSH contents and an inhibition in (Mn-SOD), (Cu-Zn SOD) and (CAT) enzymatic activities. DOX increase cytosolic and mitochondrial lipid peroxidation as attested by the MDA content. These results are reversed after one mount per os pretreatment by EEP at the amount of 100mg/kg. Propolis polyphenolic fraction protects liver tissue from oxidative stress by protecting mitochondrial functions and reinforcement of enzymatic and non enzymatic antioxidants.