Background: Hibiscus sabdariffa (HS) is used as a food flavoring agent and an herbal beverage in different parts of the world. There is a need to ascertain the safety of administration of HS in different body organs. This study investigated the comparative effect of HS in the expression levels of inflammatory cytokines, duodenal antioxidant status, and histopathology in Wistar rats. Materials and Methods: The study subjects included 30 Wistar rats (15 males and 15 females) with an average weight of 204g and 147g, respectively, and were randomly divided into three groups (n=5), A–C for each sex. Group A was given no treatment and served as the normal control group. Groups B and C received oral administration of 200mg/kg and 400mg/kg of Methanolic extract of Hibiscus sabdariffa (MEHS), respectively. The extract was administered once a day for 21 days using oral cannula. The animals were fasted overnight on the last day of MEHS administration and anesthetized using chloroform. Blood was collected from the animals for the interleukins assay procedure. The animals were sacrificed after blood collection, and the duodenum was harvested for histological processing and oxidative status determination.