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Inflammatory bowel disease is a multifactorial inflammatory condition. This study aimed to test the protective effects of <i>Spirulina platensis</i> against ulcerative colitis (UC). UC was induced in thirty-six male Wistar rats by adding dextran sulfate sodium (DSS) to their drinking water, while a control group received only drinking water. UC rats were equally-divided into six groups that received a single oral daily dose of vehicle (DSS), sulfasalazine (SSZ, 50 mg/kg/day), chloroform or the hydroalcoholic extracts of <i>Spirulina platensis</i> (100 or 200 mg/kg/day) for 15 days, and then blood and colon samples were harvested for determination of tumor necrosis factor-&#945; (TNF-&#945;), interleukin-6 (IL-6), erythrocyte sedimentation rate (ESR), myeloperoxidase (MPO), and histopathology. At the end of the study, compared to time-matched controls, UC rats showed increased TNF-&#945; (1.64-fold), IL-6 (5.73-fold), ESR (3.18-fold), and MPO (1.61-fold), along with loss of body weight (24.73%) and disease activity index (1.767 &#177; 0.216 vs. 0 &#177; 0), <i>p</i> &lt; 0.001. These effects were prevented by SSZ treatment (<i>p</i> &lt; 0.001 vs. DSS). The hydroalcoholic extract of <i>Spirulina platensis</i> dose-dependently modulated all DSS-induced inflammatory changes. However, the chloroform extract significantly lowered only IL-6 and ESR, but not TNF-&#945; or MPO levels. The protective effects of the hydroalcoholic extract of <i>Spirulina platensis</i> against experimental UC involved mitigation of DSS-induced inflammation.