Immunosuppression is a condition that causes large economic losses in the poultry industry. To investigate the effect of sulfated yeast beta-glucan on immunosuppression, two hundred and fifty 11-day-old chickens were randomly assigned to five groups, and except for the normal control group, injected with cyclophosphamide once a day for 3 successive days. At 14 days of age, sulfated yeast beta-glucan from Saccharomyces cerevisiae (sGSC) was orally administered at three doses to the chickens in three experimental groups for 14 days. On days 7 and 14 after the first sGSC dose, serum cytokine concentrations and peripheral lymphocyte proliferation were measured. Gut microbiota, organ index, and histopathological changes in the bursa were investigated on day 14. The results demonstrated that at 4 mg/kg, sGSC could significantly enhance the bursa index and IFN-γ and IL-6 concentrations, decrease TGF-β1 concentration, and promote lymphocyte proliferation; it could effectively decrease histopathological changes in the bursa and improve gut Bifidobacterium and Lactobacillus populations in cecal digesta of chickens compared with the model control group. This indicated that sGSC could effectively alleviate immunosuppression and regulate the beneficial microbiota in the gut. • The immunosuppression of chickens was induced by cyclophosphamide. • Yeast beta-glucan was modification by sulfation. • It could promote lymphocyte proliferation and IFN-γ and IL-6 secretion at 4 mg/kg. • It could enhance the bursa index, and decrease histopathological changes. • It could improve gut Bifidobacterium and Lactobacillus populations. [ABSTRACT FROM AUTHOR]