Introduction: Considering the widespread application of biological substances, such as Propolis, it is essential to identify the importance of its liver metabolism, its effects of the liver and safe doses. The aim of this study was to determine the histopathological effects of oral administration of Propolis on the liver in mice. Methods and materials: This study consisted of five experimental groups of male mice (25-30 g), including control, placebo and 3 treatment groups. Male mice (25-30 g). Each of the groups receiving Propolis extract at one of the 2000, 4000 and 8000 mg/kg concentrations. Mice were gavage fed with the alcoholic extract of Iranian Propolis once daily for 14 days. After induction of a deep anesthesia, the liver was removed and examined for histopathological changes. All the data were analyzed using SPSS software (P <0.05). Results: The results of this study indicated that chronic administration of various doses of routine Propolis induced different histopathological changes in a dose-dependent manner. These changes initiated around the central venous; furthermore, their severity was higher in this part of the liver compare to the other areas. Conclusion: Based on the results of this study, it is essential to carefully monitor the dosage and consumption duration of Propolis. Moreover, periodical examination of liver function is essential during chronic consumption of Propolis.