Lead (Pb), Nickel (Ni), Cadmium (Cd), and Antimony (Sb) are toxic metals which are capable of accumulating within vital organs of both humans and animals, inducing reactive oxygen species (ROS) production and causing severe health hazards within their biological systems. The study has been designed to clarify the hepato-renal protective effects of propolis extract against toxic metals mixture via oral administration to the males of albino rats. The concentrations of Pb, Cd, Ni and Sb as well as the activities of glutathione peroxidase (Gpx), glutathione reductase (GR), catalase (CAT), and superoxide dismutase (SOD) were all determined in the tissues of liver and kidney; while aspartate transaminase (ASAT), alanine transaminase (ALAT), total protein (TP), urea and createnine, were measured in the serum of experimental rats, besides, histopathological examinations in the tissues of liver and kidney. Metals mixture oral administration resulted in a significant increase in the concentrations of Pb, Cd, Ni and Sb within the tissues of liver and kidney of all rats from experimental groups accompanied by, a significant depletion in the levels of Gpx, GR, CAT and SOD in the same tissues. Moreover, a statistical elevation in the levels of ALAT, ASAT and urea were observed in the serum of rats from the same groups as well as, some histopathological alterations in the tissues of liver and kidney. The oral administration of propolis provided a significantly therapeutic role against metals mixture-induced hepato-renal toxicity with relative improving to histopathological changes because of its anti-oxidative action and the potentiality to nullify the deleterious effects of free radicals through reactivating the normal defense mechanism of endogenous enzymes as concluded from the present investigation.