Endometrial hyperplasia (EH) is a common gynecological condition and may progress to carcinoma. We investigated the effect of diacerein (DIA) on estradiol benzoate (EB)-induced EH and atypia. DIA (50 mg/kg/day) was administered orally to rats for 4 weeks, in the presence or absence of EH induced by intramuscular injection of EB (60 μg/100 g) three times per week for 4 weeks. We measured levels of serum total cholesterol, uterine tissue malondialdehyde (MDA), total nitrites (NOx ), superoxide dismutase (SOD) activity, caspase-3, interleukin-1b (IL-1b) immunoexpressions, and histopathology. Results showed that EB-induced EH and atypia manifested by significant increase in serum total cholesterol with increase in MDA and NOx levels. EB showed the typical histopathological changes of EH and atypia. In addition, there was reduction in SOD activity and decrease in caspase-3 immunoexpressions but increase in IL-1b immunoexpressions. DIA was able to reduce EB-induced pathological changes.