Navajo neuropathy, also known as Navajo neurohepatopathy (NNH), is a rare autosomal recessive multisystem disorder predominantly affecting full-blooded Navajo children in the southwestern United States. The condition is characterized by a triad of progressive sensorimotor peripheral neuropathy, hepatic dysfunction, and corneal anesthesia with acral mutilation. Clinical subtypes include infantile, childhood, and classic forms, each distinguished by age of onset and severity of hepatic and neurological involvement. The underlying genetic defect involves a homozygous missense mutation (R50Q) in the MPV17 gene, which encodes a mitochondrial inner membrane protein essential for maintaining mitochondrial DNA (mtDNA) integrity. Affected individuals exhibit mtDNA depletion, particularly in hepatic tissue, implicating impaired oxidative phosphorylation and energy metabolism in pathogenesis. Histopathological findings include microvesicular steatosis, cirrhosis, and severe loss of myelinated fibers in peripheral nerves. Brain MRI often reveals cerebral leukoencephalopathy, suggesting central nervous system involvement. Diagnosis is based on clinical criteria, imaging, liver biopsy, and genetic testing. Management remains supportive, with liver transplantation considered in cases of fulminant hepatic failure. Despite intervention, prognosis is poor, with most patients succumbing to liver failure or complications of neuropathy in early childhood. The disease exemplifies a founder effect within the Navajo population and expands the phenotypic spectrum of mitochondrial DNA depletion syndromes.