Collectively, our study uncovers a novel and broad-spectrum immunomodulatory function of ANXA2, wherein it dampens antiviral innate immunity by sabotaging key protein-protein interactions (MDA5-MAVS or MAVS-TRAF3) within the RLR pathway, thereby presenting a potential target for developing antiviral strategies.<h4>Importance</h4>Subsequent to RNA viral infection, a series of complex cascade reactions are initiated, leading to the production of type I interferons and, consequently, the resistance of the organism to viral infection. Here, TRAF3 is linked to viral infectious disease.