Sea cucumber is a traditional Chinese tonic with various bioactivities. This study systematically investigated the immunomodulatory effect of saponins extracted from sea cucumber residues (SCRSS) at doses of 2.5, 5.0 and 10.0 mg/(kg m_b·d) on immunosuppressive mice. The results showed that SCRSS at a dose of 5.0 mg/(kg m_b·d) increased the body mass, spleen index, and thymus index by 15.3%, 23.8%, and 39.8%, respectively, compared to the model control group, and it also significantly increased the phagocytic index in immunosuppressive mice (P < 0.01). Moreover, All the doses of SCRSS remarkably increased serum cytokine levels, promoted the proliferation activity of splenic lymphocytes and peritoneal macrophages. Importantly, the middle dose (5.0 mg/(kg m_b·d)) of SCRSS was more effective to upregulate the expression of nucleotide binding and oligomerization domain (NOD)1, NOD2, receptor interacting protein 2 (RIP2) and nuclear factor (NF)-κB in immunosuppressive mice. Thus, SCRSS may be used as a functional food supplement to improve immunity.