Fucoidan is a rich source of medicinally active immunostimulants that possess various pharmacological properties. This study examined the potential impact of fucoidan on the hematic indicators and antioxidative responses of Nile tilapia fed diets contaminated with aflatoxin B1 (AFB1). Fish (60 ± 6.1 g) were allocated to five groups; the first (control) and second groups were fed 0% or 1% fucoidan–supplemented diets without AFB1 contamination, while the third, fourth, and fifth groups were fed diets contaminated with AFB1 and supplemented with 0%, 0.5%, and 1% fucoidan, respectively. After 30 days, fish fed AFB1 showed high ALT, AST, ALP, cholesterol, urea, and creatinine levels; furthermore, total blood protein and tissue (liver, kidney, and gill) glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) activity significantly (P ≤ 0.05) decreased in fish fed AFB1, while tissue malondialdehyde significantly increased (P ≤ 0.05). Interestingly, fish fed fucoidan showed decreased ALT, AST, ALP, cholesterol, urea, and creatinine, as well as increased blood protein, GSH, GPx, SOD, and CAT activity. The results suggested that fucoidan is capable of inducing protective activity against AFB1 toxicity in Nile tilapia by enhancing the serum biochemical and tissue antioxidant responses of fish.