Zearalenone (ZEN), a mycotoxin produced by several Fusarium spp., is most commonly found as a contaminant in stored grain and has chronic estrogenic effects on mammals. ZEN and its metabolites have anabolic activities and induced severe stress on liver, kidney and immune system. The aims of the current study were twofold: (1) to investigate the changes in serum biochemical, immunological parameters and histological picture of spleen in ZEN-treated Balb/c mice and (2) to evaluate the safety and efficacy of HSCAS to ameliorate the deleterious effects of ZEN. The results indicated that a single dose of ZEN (40 mg/kg bw) significantly reduced total cholesterol, HDL, LDL, triglycerides, total protein, albumin, total count of WBCs, immunoglobulin profile (Ig A and Ig G) and T-cells subtypes (CD3+, CD4+, CD8+ and CD56+). Whereas, it significantly increased uric acid and urea and induced degenerative changes in the spleen tissues. Mice treated with HSCAS alone (400 mg/kg bw) were comparable to the control regarding all the tested parameters. While HSCAS at levels 600 and 800 mg/kg bw caused changes in some tested biochemical parameters. The combined treatment of ZEN and the lowest tested dose of HSCAS (400 mg/kg bw) showed a significant improvement of the immunological, biochemical and histological parameters. It could be concluded that HSCAS was effective in the protection against the hazards of ZEN at a dose as low as 400 mg/kg bw. These results supported our hypothesis that HSCAS tightly-bind and immobilized ZEN resulted in reduction of toxin bioavailability in animal's gastrointestinal tract.