Cyclophosphamide is a commonly used anticancer drug, and immunosuppression is one of the most common side effects. How to recover the immunological function is important for cyclophosphamide-treated patients. In the present study, Phellodendri Cortex polysaccharides (CPP) could enhance the proliferation of mouse spleen lymphocytes in vitro. The immunoregulatory function of CPP was then investigated in cyclophosphamide-induced immunosuppressed mice. In CPP-treated groups, mice were orally treated with CPP at doses of 1, 0.5, and 0.25 g/kg bodyweight from 1 to 11 d, respectively. The cyclophosphamide was administrated in CPP and cyclophosphamide groups from 12 to 14 d. In the cyclophosphamide and normal control groups, the mice received equal volume of saline from 1 to 14 d. The results showed that CPP (1 g/kg) could significantly increase the bodyweight of mice, even during cyclophosphamide treatment. The organ coefficients of the spleen and thymus were recovered by CPP treatment. CPP upregulated the contents of cytokines (IL-2, IL-6, IFN-γ, and TNF-α) in serum, which were downregulated by cyclophosphamide. The mRNA levels of these cytokines were also elevated by CPP treatment in the spleen. Cyclophosphamide upregulated the expressions of NF-κB p65, TLR4, and MyD88, suggesting that the NF-κB signaling pathway was activated by cyclophosphamide. After CPP treatment, it was recovered to normal level. These results indicated that CPP alleviated the cyclophosphamide-induced immunosuppression.