Doxorubicin (DOX) is a chemotherapy medication that is used to treat different types of cancers. Propolis is commonly used as a hepatoprotective agent against oxidative stress. Therefore, the present study was designed to investigate the possible protective role of the Egyptian propolis extract (EPE) against DOX-induced hepatic toxicity in rats. The study was carried out on forty male adult albino rats divided into four groups (control group): received normal saline by oral gavage daily for 28, (EPE group): received EPE (200 mg /kg) daily by oral gavage for 28 days. (DOX group): rats were injected once with DOX (20 mg/kg) intraperitoneally on the 24th day (EPE treated DOX group): received EPE (200 mg /kg) daily by oral gavage for 28 days and injected with DOX 20 mg/kg intraperitoneally on the 24th day. Our results revealed that liver enzymes, MDA, TNFα, interleukin -1β (IL-1β) and IL-6 and caspase-3 were significantly increased in DOX group compared with control, while EPE treated DOX group showed significant decrease. Catalase and superoxide dismutase were significantly decreased in DOX group compared with control while EPE treated DOX group showed significant increase. Moreover, gene expression of TNF α, nuclear factor erythroid 2–related factor 2 (NRF-2), heme oxygenase -1 (HO-1) have been elevated significantly in DOX group when compared with control and their mRNA levels have been downregulated significantly by EPE treatment while EPE treatment has upregulated gene expression of BCL-2. Conclusion: our results raised the idea that EPE protecting the liver from DOX-related oxidative and apoptotic effects.