Multiple sclerosis (MS) is the most recognized CNS autoimmune demyelinating disease, characterized by neuroinflammation, myelin loss, and axonal damage. Due to clinical overlap with several disorders such as systemic autoimmune diseases (SADs), which can closely resemble MS, the diagnostic process can be challenging. SADs with CNS involvement can present with neurological symptoms such as transverse myelitis, optic neuritis, and white matter lesions. This diagnostic uncertainty contributes to a significant rate of misdiagnosis which can lead to improper treatment, worsening symptoms and increasing disability. In this review we discuss the physiology of myelin in the CNS, the pathophysiology of MS and other immune-mediated demyelinating diseases that can mimic MS. We also discuss similar presentations between MS and MS-like clinical entities, and their appropriate treatment regimes. SADs and other clinical entities are key MS mimickers, significantly complicating diagnosis at a first neurological episode. Careful clinical evaluation, imaging, and exclusion of alternative diagnoses are crucial to avoid misdiagnosis. Understanding the subtle distinctions between MS and SADs and looking out for, and further investigating atypical presentations, is vital for ensuring accurate diagnosis and proper treatment, thereby improving patient outcomes and reducing unnecessary disability.