Infectious diseases of the central and peripheral nervous system may present with clinical, radiological, and laboratory findings that closely resemble those seen in multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and other autoimmune disorders. This chapter provides a comprehensive review of a wide spectrum of neuroinfectious agents—including bacterial, viral, parasitic, and fungal pathogens—that may mimic or coexist with inflammatory demyelinating diseases. Key conditions discussed include brain abscesses, neurobrucellosis, coronavirus disease 2019 (COVID-19)-associated neurological syndromes, Epstein–Barr virus (EBV) encephalitis, hepatitis C virus (HCV)-associated myelitis and neuropathy, herpes simplex virus (HSV) encephalitis, human immunodeficiency virus (HIV)-associated vacuolar myelopathy, human T-lymphotropic virus type I (HTLV-1)-associated myelopathy, Lyme neuroborreliosis, progressive multifocal leukoencephalopathy (PML), syphilis, tuberculosis, varicella zoster virus (VZV), or Whipple’s disease. For each infection, the chapter outlines epidemiology, pathogenesis, clinical presentation, imaging features, cerebrospinal fluid (CSF) findings, diagnostic strategies, and treatment options. Emphasis is placed on identifying red flags that help differentiate infectious from autoimmune processes, such as fever, rapid progression, atypical lesion morphology or distribution, and specific laboratory findings (e.g., pathogen polymerase chain reaction [PCR], serological testing, or matched oligoclonal bands [OCB]). Early recognition of infectious etiologies is crucial, as many conditions require pathogen-specific antimicrobial or antiviral therapy and may worsen with immunosuppressive treatment. This chapter offers practical guidance for clinicians navigating complex cases at the interface of infection and autoimmunity.