||Powerful phagocytosis by macrophages constitutes the first line of defense of the innate immune response. Macrophages are scavengers of cellular debris and invading pathogens. So far, differences in the phagocytic function of macrophages in different chicken breeds are rarely reported, and molecular mechanisms underlying phagocytosis remains poorly understood. In this study, comparison of differences in phagocytosis of primary macrophages and integrated analysis of mRNA expression profiles and whole-genome sequencing were conducted in Dagu chicken and Wenchang chicken. The results revealed Dagu chicken, compared to Wenchang chicken, was more resistant to salmonella challenge, particularly, displayed a significantly higher phagocytic ability at 14 and 28 days old, respectively. Furthermore, the comparative analysis of mRNA expression profiles of macrophages of two breeds in 28 days old revealed that 1136 differentially expressed genes (DEGs) were identified and 22 DEGs (e.g., H2AFZ, SNRPA1, CUEDC2, S100A12) were found to be hub genes regulating the phagocytosis by participating in different immunological biological signaling pathways. Besides, our results revealed many DEGs and hub genes were under strong selection between two breeds, and among strong selected genes, only H2AFZ gene was intersection of DEGs and hub genes. We provided comprehensive function comparison and transcriptomic profiles of macrophages in two Chinese native chicken breeds, and the identification of key genes will expand our understanding of the molecular mechanism of macrophage phagocytosis.