Background: Overproduction of reactive oxygen species (ROS) causes increased lipid peroxidation, decreased intestinal epithelial barrier integrity, and ultimately mucosal disruption and ulceration. Several studies have confirmed the antioxidant, antiinflammatory, and immunomodulatory properties of Spirulina Platensis (SP), edible blue -green algae, in various inflammatory diseases. In addition, natural honey, a source of phenolic and flavonoid compounds, is a powerful antioxidant, which can help prevent chronic oxidative stress and subsequent inflammation. Objectives: In this study, we examined and compared the protective effects of SP and honey on ulcerative colitis induced by acetic acid (AA) in rats. Methods: Forty male rats were allocated into five groups (N = 8) and received pretreatment for 32 consecutive days. The administrations were as follows: group 1 (control) and group 2 (AA-colitis group): normal saline, group 3: 1 ml honey/day, group 4: 1 ml honey/day plus 1 g/kg SP, and group 5: 1 g/kg SP. Colitis was induced on the 30th day in groups 2 to 5. On day 32, the clinical activity was determined and anesthetized animals were sacrificed. Serum interleukin-6 (IL-6), IL-1β, tumor necrosis factor-α (TNF-α), glutathione peroxidase (GPx), reduced glutathione (GSH), total antioxidant capacity (TAC), superoxide dismutase (SOD), colonic tissues myeloperoxidase (MPO), prostaglandin E2 (PGE2), malondialdehyde (MDA), nitric oxide (NO), and colonic weight/length ratio were determined. In addition, histopathological changes of the colon were observed microscopically.