It was found that APS is a superior regulator of mammalian macrophages. However, the immunomodulatory effects of APS on chicken macrophages remain largely unknown.This study evaluated the immunomodulatory activity of APS on HD11 macrophagesand to determine the underlyingmechanism. The mRNA levels of M1/M2 polarizing molecules, cytokines, TLRs and NF-κB p65 in HD11 macrophages were determined by reverse transcription-quantitative PCR analysis. Western-blotting was used to determine the effects of APS on MyD88, PI3K, ERK, P-ERKand AKT protein expression. Remarkably, APS promoted the gene expression of M1-type polarizing molecules and inhibited the gene expression of CD206. APS significantly promoted the gene expression of IL-8 and IL-10, without affecting TNF-a. APS showed a significant inhibitory effect on TLR2 and TLR4 gene expression. Moreover, 50 µg/mL APS significantly induced the protein levels of MyD88, ERK, and inhibited the protein level of p-ERK. In addition, 200 µg/mL APS could significantly enhance the protein levels of PI3K, ERK, AKT and the mRNA level of NF-κB p65. These results suggested that APS acts as an immunomodulator which shows differential dose-dependent effects on chicken macrophages. With increased APS dose, the main signaling pathway involved in its immunoregulatory effects alters from the TLR2-MyD88-ERK to the TLR2/4-PI3K-AKT pathway.