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In this review, we critically examine the therapeutic potential of selected antimicrobial classes, including tetracyclines (e.g., minocycline), macrolides (e.g., azithromycin), antimalarial agents (e.g., chloroquine\/hydroxychloroquine), sulfones (e.g., dapsone), and antiparasitic agents (e.g., ivermectin), in non\u2010infectious neurological diseases. We performed a narrative review of pre\u2010clinical and clinical studies to investigate the effects of these agents on the main neuropathological mechanisms, such as neuroinflammation, oxidative stress, mitochondrial dysfunction, impaired autophagy, and gut\u2013brain axis dysregulation. The available evidence suggests that many of the antimicrobial agents have beneficial effects in a number of neurological disorders, including Alzheimer's disease, Parkinson's disease, epilepsy, stroke, and traumatic brain injury. These agents have been shown to modulate microglia activation, to inhibit production of pro\u2010inflammatory cytokines, and to alter intracellular signaling pathways, including nuclear factor kappa\u2010light\u2010chain\u2010enhancer of activated B cells. Furthermore, by reshaping the gut microbiota, antimicrobials modulate immune signaling, alter neurotransmitter levels, and compromise blood\u2013brain barrier integrity\u2014thereby positioning the gut\u2013brain axis as central to their mechanism of action. Repurposing antimicrobial agents is a pragmatic and novel approach to treat complex neurological disorders with available approved drugs. Despite the encouraging evidence, we must carefully manage challenges such as antimicrobial resistance, off\u2010target effects, and regulatory considerations. Further well\u2010designed clinical trials are essential to validate their long\u2010term safety and efficacy in neurodegenerative and neuroinflammatory diseases.<\/jats:p>","DOI":"10.1002\/nep3.70042","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T13:20:09Z","timestamp":1789132809000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Repurposing antimicrobial agents for neuroprotection: Mechanisms, clinical potential, and challenges"],"prefix":"10.1002","author":[{"given":"Mohammad Amin","family":"Manavi","sequence":"first","affiliation":[{"name":"Experimental Medicine Research Center Tehran University of Medical Sciences Tehran Iran"},{"name":"Department of Toxicology and Pharmacology, Faculty of Pharmacy Tehran University of Medical Sciences Tehran 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