As an important edible traditional Chinese medicine, Codonopsis pilosula has good immunomodulation effects. This study focuses on C. pilosula oligosaccharides (CPO), which are the sweetness components of C. pilosula. CPO were obtained through systematic separation and purification (the yield is 14.3%), and the effect of CPO on the immunological activities of immunocompromised mice induced by cyclophosphamide (CTX) was evaluated. The results showed that CPO could increase immune organ indices, phagocytic index and immunoglobulin contents, stimulate the proliferation of splenic lymphocytes (coordinating with ConA and LPS), enhance the earlap swelling of the DTH reaction, promote the production of NO and cytokines (IL-2 and IFN-γ) and upregulate the expression of the corresponding mRNA. In addition, CPO upregulated the protein expression of phosphorylated p38, phosphorylated ERK1/2 and phosphorylated JNK, which indicated that CPO might exert immunomodulatory effects through the MAPK signaling pathway. These findings indicated that CPO are important immunomodulatory components in C. pilosula and could be developed as immunomodulators in medicine or functional food areas.