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ABSTRACT Herpes simplex virus-1 (HSV-1) has evolved mechanisms to evade the host immune system and limit the antiviral effects induced by interferon (IFN) produced by local epithelial and immune cells. In this study, we determined the effects of type I, II, and III IFNs on HSV-1 release from sensory axons. Using compartmentalized microfluidic devices separating axons from the neuronal cell bodies, we showed that treating axons with type I (IFNα and IFNβ), type II (IFNγ), and type III (IFNλ) IFNs inhibited the release of HSV-1 from axons, without altering the anterograde axonal transport of viral components. Furthermore, we showed that only type II IFN induced a cell-wide response following axonal treatment, with phosphorylated STAT1 and STAT3 present along axons and in the neuronal cell body, whereas type I and III IFNs only induced a local STAT1 and STAT3 response in axons. We also showed that HSV-1 infection alone, in the absence of exogenous IFN, activated STAT1 and STAT3 in both neuronal cell bodies and along axons. However, HSV-1 infection restricted the translocation of pSTAT1 and pSTAT3 to the nucleus even in the presence of IFNs, suggesting viral evasion mechanisms are involved in limiting the IFN response in the neuronal cell body. Overall, our study indicates a key and greater antiviral role of IFNs in inhibiting HSV-1 release from axon termini than in the ganglia during recurrent infections and identifies a novel intervention site, the neuro-epidermal junction, for the development of new immunotherapies. IMPORTANCE Herpes simplex virus-1 (HSV-1) is a human pathogen known to cause cold sores and genital herpes. HSV-1 establishes lifelong infections in our sensory neurons, with no cure or vaccine available. HSV-1 can reactivate sporadically and travel back along sensory nerves, where it can form lesions in the oral and genital mucosa, eye, and skin, or be shed asymptomatically. New treatment options are needed as resistance is emerging to current antiviral therapies. Here, we show that interferons (IFNs) are capable of blocking virus release from nerve endings, potentially stopping HSV-1 transmission into the skin. Furthermore, we show that IFNγ has the potential to have widespread antiviral effects in the neuron and may have additional effects on HSV-1 reactivation. Together, this study identifies new targets for the development of immunotherapies to stop the spread of HSV-1 from the nerves into the skin.