In the present study, we have evaluated the hepatoprotective and antioxidant effects of Spirulina fusiformis (a cyanobacterium-family-Oscillatoriaceae) against acetaminophen-induced hepatotoxicity in mice. For comparison purpose, results were compared with those for silymarin, a standard hepatoprotective drug. Activities of liver marker enzymes (glutamate-oxaloacetate transaminase, glutamate-pyruvate transaminase, and alkaline phosphatase) and inflammatory mediator tumour necrosis factor-alpha (TNF-α) were estimated in serum, while lipid peroxidation and antioxidant status (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-s-transferase and glutathione) were determined in liver homogenate. Acetaminophen induction (900mg/kg b.wt) significantly increases the levels of liver marker enzymes, TNF-α, and lipid peroxidation, and caused the depletion of antioxidant status. Treatment of Spirulina fusiformis (800mg/kg/b.wt) to acetaminophen challenged mice resulted in decreased liver marker enzymes activity, TNF-α and lipid peroxidation levels with increase in antioxidant status. Our study clearly demonstrate that Spirulina fusifomis shows hepatoprotective effect through its antioxidant activity on acetaminophen-induced hepatotoxicity in mice. © IJIB, All rights reserved.