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, β-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 β-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-1β, IFN-α, IFN-β, TNF-α, RIG-I, TLR3
, and
TLR7
gene expression. In summary, chlorogenic acid, β-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.