The abuse of antibiotics for agricultural purposes has been under scrutiny. Therefore, there is an urgent need to find antibiotic substitutes in animal production. The effects of chlorogenic acid, beta-D-Glucan, astragalus flavone, CpG-DNA, and chicken IgG on spleen antioxidant capacity, apoptosis, and the immune response in Shaoxing ducklings were investigated in this study. The ducklings treated with beta-D-Glucan, astragalus flavone, CpG-DNA, and chicken IgG showed significant reduction in catalase and superoxide dismutase activities. The five immunopotentiators facilitated caspase 3 expression and reduced Bcl2 expression in the spleen. Compared to the control group, the protein level of COX2 was significantly upregulated in the chlorogenic acid, CpG-DNA, and chicken IgG groups. The protein level of iNOS expression was significantly improved in all immunopotentiator groups, except for the astragalus flavone group. The five immunopotentiators induced IL-1 beta, IFN-alpha, IFN-beta, TNF-alpha, RIG-I, TLR3, and TLR7 gene expression. In summary, chlorogenic acid, beta-D-Glucan, astragalus flavone, CpG-DNA, and chicken IgG, as immunopotentiators, improved the innate immune response in the ducklings, which not only provides a new avenue for the development of efficient approaches to prevent pathogen infections, but also offers an alternative to antibiotics in animal production.