The human oral cavity hosts a diverse and dynamic microbiome comprising more than 700 microbial species, which plays a crucial role in maintaining oral and systemic health. Oral dysbiosis, defined as disruption of this microbial balance, has been increasingly implicated not only in periodontal disease but also in the pathogenesis of orofacial pain and neurodegenerative diseases. Key pathogens, such as Porphyromonas gingivalis, Treponema denticola, and Fusobacterium nucleatum, have been proposed to release virulence factors, including lipopolysaccharides and gingipains, which may activate immune pathways and nociceptors, thereby driving peripheral sensitization and neuroinflammation. These organisms have also been suggested to breach mucosal and vascular barriers, enter the systemic circulation, and, in some cases, access the central nervous system. Evidence has linked oral pathogens to Alzheimer’s disease, Parkinson’s disease, autism spectrum disorder, and multiple sclerosis. Notably, P. gingivalis and its gingipains have been identified in postmortem brain tissue from patients with Alzheimer’s disease, with proposed roles in neuroinflammation and amyloid plaque formation. Salivary microbial alterations in burning mouth syndrome and temporomandibular disorders further highlight the influence of the oral microbiome on neuropathic pain. Therefore, the oral-gut-brain axis represents a novel and promising area of investigation, offering potential diagnostic biomarkers and targeted microbial therapies for the management of chronic orofacial pain and neurological disorders.