Background: Spirulina is a biomass of cyanobacteria (blue-green algae) that can be consumed by humans and other animals. It is a type of microscopic algae in the shape of a perfect spiral coil. It is one of the many dietary supplements commercially available. It contains an abundant amount of essential amino acids, fatty acids, protein, vitamins, minerals, and pigments. Spirulina has many health benefits in preventing or managing hypercholesterolemia, hyperglycemia, cardiovascular diseases, diabetes, and other metabolic disease. Aim: The principal objective of this study was to estimate the possible side effects of two doses (500 and 1000 mg/kg b. wt) of Spirulina supplementation on as the liver, kidney and testis of rats. Materials and Methods: Adult male albino rats (Rattus norvegicus) weighing 120-140g were divided into three groups, G1: control; G2: treated with Spirulina at 500 mg/kg b. wt; and G3: treated with Spirulina at 1000 mg/kg b. wt. The administration was undertaken by gastric tube for 21 days. Biochemical analysis was done for measuring the blood levels of ALT, AST, urea, and creatinine. The liver, kidney and testis were excised, sectioned, and stained with different histological and histochemical stains for histopathological studies. Results: Spirulina induced many histological changes in the hepatic, renal, and testicular tissues, as well as biochemical changes in a dose-dependent manner. Conclusion: Uptake of uncontrolled supplementary doses of Spirulina may induce biochemical dysfunction and histopathological changes in some vital organs. Therefore, caution must be taken at using Spirulina as a food supplement. In fact, further biochemical and histopathological studies on its effect on other vital organs are needed for optimal dose-finding that should be considered for both efficacy and toxicity of Spirulina on the human body.