The activation of type I interferons has long been reported to regulate pain, but the precise mechanism has remained unclear. We tested the hypothesis that type I interferons are critical pain regulators and function via a neuronal mechanism. Sensory, motor, and behavioral testing in addition to immunohistochemistry were performed on type I interferon receptor knockout (Ifnar1 KO) and wild type (WT) mice. Heightened sensitivity in KO mice suggests an importance of type I interferons in regulating pain under basal conditions. The lack of any difference in motor performance and quantity of nerve fibers in tissue of WT and Ifnar1 KO, along with RNA scope, support a neuronal-specific mechanism of interferons in regulating pain. These findings suggest that type I interferons are critical in regulating both pain and neuroinflammation by a neuronal mechanism, even under normal, healthy conditions. These findings redefine our understanding of the role of interferons in pain and could translate to improved treatment of a heterogeneous array of chronic pain.