The emergence of jaws in early vertebrates introduced a novel feeding apparatus and potent oral defenses but also increased the risk of physical injury and pathogen exposure. Innate immunity and inflammation constitute the body’s first line of defense against invading microbes and tissue damage, aiming to eliminate threats and restore internal homeostasis. Interferon regulatory factor 5 (IRF5) plays a critical role in orchestrating innate immunity and inflammation by regulating the transcription of genes that encode type I interferons (IFNs) and pro-inflammatory cytokines. As the closest member of IRF5, IRF6 is involved in jaw development in humans and mice. However, the evolution of IRF5 and IRF6 has remained poorly understood. We have identified the IRF5 and IRF6 genes in cartilaginous fish, including sharks. As cartilaginous fish represent one of the oldest surviving jawed vertebrate lineages, the presence of these genes suggests that they have ancient origins potentially dating back hundreds of millions of years to early jawed vertebrates. Furthermore, our analysis shows that IRF5 has conserved nuclear export sequences and phosphorylation sites for activation throughout evolution from cartilaginous fish to humans, indicating that these regulatory elements evolved early and have been maintained across jawed vertebrates. Additionally, the shift in the subcellular localization of IRF5 from the nucleus to the cytosol, and of other interferon-related IRFs, aligns with functional enhancements of IRFs in innate immunity and the emergence of IFNs across jawed vertebrates. This analysis implies that the evolution of jaws may have driven the emergence of new IRF members, the expansion of their functions, and the development of a unique inflammation and innate immune system in vertebrates.