Fucoidans (FUCs) are sulfated polysaccharides that have a wide range of bioactivities. The current study was designed to evaluate the antioxidant potential of FUC against microcystin-LR (MC-LR)-induced toxicity. Five mice groups ( n  = 8) were used. Group 1 received saline, Group 2 received oral FUC 100 mg/kg/day for 21 days, Group 3 received i.p. MC-LR 10 μg/kg/day for 14 days, Group 4 received MC-LR plus FUC 50 mg/kg/day, and Group 5 received MC-LR plus FUC 100 mg/kg/day. The present study showed that MC-LR administration was associated with significant increases ( p  < 0.01) in serum concentrations of hepatic (aspartate transferase, alanine transferase, and alkaline phosphatase), renal (urea and creatinine), and cardiac (creatine kinase and CK-MB) injury biomarkers, as well as serum lactate dehydrogenase, cholesterol, and pro-inflammatory cytokines (interleukins-1β and 6, and tumor necrosis factor-α), compared with the control group. Further, MC-LR-intoxicated mice exhibited significantly higher ( p  < 0.01) hepatic, renal, and cardiac tissue levels of malondialdehyde and nitric oxide, as well as lower tissue levels of reduced glutathione and activities of glutathione peroxidase, superoxide dismutase, and catalase enzymes in comparison with control mice. Treatment by FUC significantly ameliorated all the above-mentioned alterations in a dose-dependent manner with frequent restoration of the normal ranges in the FUC 100 mg/kg/day dose group. Moreover, treatment by FUC alone at 100 mg/kg/day was not associated with significant negative alterations in the assessed biochemical parameters, highlighting its safety at this dose. In conclusion, treatment by FUC significantly ameliorated organ injury, induced by MC-LR in mouse hepatic, renal, and cardiac tissues.