Sulfated polysaccharides from marine seaweeds are receiving continuous attention owing to their wide therapeutic applications and are known to inhibit free radical generation. It has been well known that mitochondria are the major sources as well as the target of free radicals. The renal tubules have high density of mitochondria and therefore show structural and functional defects in acute renal failure. Hence, the present study is designed to appraise the mitochondrial status during Cyclosporine A (CsA)-induced nephrotoxicity and the effect of sulfated polysaccharides over it. Sulfated polysaccharides (5 mg/kg body weight, subcutaneously) treatment significantly prevented the CsA-induced (25 mg/kg body weight, orally) mitochondrial damage. CsA-induced mitochondrial oxidative stress in rat kidney was evident from increased reactive oxygen species level, decreased antioxidant defense system, coupled with enhanced lipid peroxidation. Further, the activities of tricarboxylic acid cycle and electron transport chain enzymes were decreased in CsA-induced rats, along with a significant increase in the activities of urinary enzymes, thus indicating renal tubular injury. Ultrastructural changes were also in accord with the above aberrations. The above abnormalities were favorably modulated by sulfated polysaccharides supplementation, thus highlighting the significance of sulfated polysaccharides in preventing the renal mitochondrial dysfunction allied with CsA-provoked nephrotoxicity.