Avian influenza viruses (AIVs) are potential pandemic of global concern, posing a major threat to both the poultry industry and human health. Host factors play a key role in the replication of AIVs, while the function of complement component 4 binding protein, membrane (C4BPM) in this process is still unclear. This research reports that C4BPM promotes replication of H5N1 and H9N2 AIVs by inhibiting type I interferons (IFNs). H5N1 and H9N2 AIVs infection up-regulate the expression of C4BPM in chicken embryo fibroblast cells (DF-1). To verify the role of C4BPM in replication of AIVs, C4BPM knockout (C4BPM-KO) and stable overexpressing (C4BPM-overexpressing) DF-1 cells were generated using lentivirus-mediated CRISPR/Cas9 gene editing technology and molecular cloning strategies. Replication of H5N1 and H9N2 AIVs were promoted in C4BPM-overexpressing DF-1 cells with inhibited expression of type I IFNs (IFN-α, IFN-β), protein kinase R (PKR), cholesterol 25-hydroxylase (CH25H), interferon regulatory factor (IRF) 3, and mitochondrial antiviral signaling protein (MAVS) compared to that of the DF-1 cells. However, the replication of H5N1 and H9N2 AIVs in C4BPM-KO DF-1 cells were inhibited with the increased expression of above related anti-viral factors. Further results showed that C4BPM did not affect viral adsorption, while, promote the entry of H5N1 and H9N2 AIVs. These results expand the range of host factors regulating replication of AIVs and suggest that C4BPM is a promising target for anti-viral agent.