The central nervous system (CNS) must defend itself against bacterial and fungal infection while also minimizing inflammatory infiltration and maintaining normal cognitive function. Since the CNS is an immune privileged site, inducible innate immune defense mechanisms endogenous to the CNS likely play a key role in this regard. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide that regulates neurodevelopment, emotion, and stress responses via G-protein coupled receptors. While PACAP is known to interact with the immune system, its significance in host defense in the brain or in other tissues like the skin and the kidney is not known. Here, we use a machine learning classifier to identify PACAP as a tissue resident neuropeptide optimized for “clean” CNS defense against pathogens that traditionally require clearance by Th17 neutrophil-based responses. Synchrotron x-ray scattering, antimicrobial assays, and mechanistic fingerprinting enable us to profile precisely how PACAP exerts bactericidal activity against drug-resistant bacteria via multiple synergistic mechanisms including membrane permeabilization, disruption of cellular energetics, and activation of cell death pathways. Most importantly, we find that PACAP is strongly and selectively induced up to 50-fold in the brain and other tissues in mouse models of S. aureus and Candida infections. Interestingly, PACAP is also expressed by cutaneous peripheral neurons and likely plays a role in host defense of the skin. We are currently exploring how PACAP modulates the skin microbiome and cutaneous inflammation.