The innate immune system is critical for early detection of invading viruses and for initiating cellular host defense countermeasures, which include the production of interferons. Ankyrin repeat domain 22 (ANKRD22) encodes a protein of 191 amino acids containing 2 ankyrin repeating domain, and its biological function was unknown. In this study, we find that ANKRD22 expression can be significantly induced in human peripheral blood mononuclear cells (PBMCs) by DNA virus herpes simplex virus-1 (HSV-1) and RNA virus respiratory syncytial virus (RSV) as well as IFN-α and IFN-γ. Its induction in PBMCs by viruses is largely a secondary effect of virus-induced interferons. We further demonstrate that ANKRD22 was majorly induced in monocytes and dendritic cells from PBMCs. Over-expression of ANKRD22 confers protection against HSV-1 and RSV infection in multiple tested cell lines. Vice versa, inhibition of ANKRD22 leads to enhanced HSV-1 and RSV replication in host cells. Furthermore, we identifies that ANKRD22 specifically interacts with STING, a critical protein function in multiple antiviral innate immune pathways. ANKRD22 by itself can only slightly induce type I IFNs IFN-α and IFN-β, and can’t induce type III IFN IL-29. However, it significantly synergizes STING-induced both type I and type III interferon production. Collectively, our studies indicate that ANKRD22 plays an important role for host defense against both DNA and RNA viruses by optimizing STING’s function on inducing type I and type III IFNs.