Autoimmune and inflammatory multisystem diseases with neurological manifestations represent a complex and heterogeneous group of disorders that can mimic multiple sclerosis (MS) and other central nervous system (CNS) pathologies. This chapter reviews the epidemiology, clinical spectrum, and neuroimaging characteristics of several key conditions, including antiphospholipid syndrome (APS), Behçet’s disease, celiac disease, Churg–Strauss syndrome (eosinophilic granulomatosis with polyangiitis), Cogan’s syndrome, cytotoxic T-lymphocyte antigen 4 (CTLA-4) haploinsufficiency, immunoglobuin G4 (IgG4)-related disease, inflammatory bowel disease, rheumatoid arthritis, sarcoidosis, Sjogren’s syndrome, Susac’s syndrome, or systemic lupus erythematosus (SLE). These diseases often involve systemic autoimmune processes with CNS complications such as stroke, myelitis, optic neuropathy, pachymeningitis, encephalopathy, and inflammatory pseudotumors. The chapter emphasizes the diagnostic pitfalls arising from overlapping features with MS, highlighting distinguishing clinical signs, cerebrospinal fluid profiles, antibody panels, and neuroimaging red flags. A detailed discussion is provided on MRI lesion patterns, spinal cord imaging, and laboratory findings, including cerebrospinal fluid (CSF) oligoclonal bands, antinuclear antibodies (ANA) titers, and autoantibody profiles. Treatment strategies vary and include immunosuppression, anticoagulation, corticosteroids, or targeted biologics depending on disease pathogenesis. Early recognition and accurate differentiation from demyelinating diseases are crucial to avoid misdiagnosis and implement disease-specific therapies. This chapter provides clinicians with a comprehensive guide to the clinical, radiological, and immunological features of major autoimmune and inflammatory multisystem diseases affecting the nervous system.