Acquired metabolic and nutritional disorders represent an important, often underrecognized cause of neurological syndromes, some of which can mimic inflammatory demyelinating diseases such as multiple sclerosis (MS) or neuromyelitis optica spectrum disorders (NMOSD). This chapter provides an overview of key metabolic and nutritional etiologies associated with myelopathy, encephalopathy, neuropathy, and other central or peripheral nervous system manifestations. Conditions discussed include osmotic demyelination syndrome (central pontine and extrapontine myelinolysis), vitamin B12 and folate deficiency, copper deficiency and zinc overload, Marchiafava–Bignami disease, nitrous oxide-induced myelopathy, vitamin E deficiency, Wernicke encephalopathy, and some rare entities such as lathyrism. The clinical spectrum of these disorders ranges from asymptomatic states to severe, life-threatening complications, including spastic paraparesis, sensory ataxia, cognitive decline, optic neuropathy, and encephalopathy. Magnetic resonance imaging (MRI) features—such as inverted “V” sign in posterior spinal cord columns, symmetric corpus callosum lesions, or typical brainstem and diencephalic lesions—serve as diagnostic clues. Laboratory evaluation, including vitamin levels, metabolic markers (e.g., homocysteine, methylmalonic acid), and hematological parameters, supports diagnostic confirmation. Cerebrospinal fluid analysis is generally normal or nonspecific, but helpful to exclude inflammatory etiologies. Importantly, many of these conditions are potentially reversible with appropriate vitamin or mineral supplementation and cessation of underlying triggers (e.g., alcohol, nitrous oxide, zinc overload). However, delayed recognition may result in irreversible neurological damage. This chapter emphasizes the importance of early detection, comprehensive diagnostic evaluation, and targeted treatment to prevent misdiagnosis and improve patient outcomes.