Mutations in myelin regulatory factor (MYRF) are linked to demyelinating disorders. We report a 38‐year‐old male who developed acute symmetric leukoencephalopathy mimicking a stroke following an influenza A virus infection. While clinical symptoms markedly improved with corticosteroids, MRI revealed persistent white matter lesions, contrasting with the known phenotype of MYRF‐related mild encephalopathy with reversible myelin vacuolization (MMERV). Genetic analysis identified a novel MYRF variant (c.2204G>A, p.Gly735Asp) in its C‐terminal domain, with familial cosegregation confirming autosomal dominant inheritance. This case demonstrates that viral infections can trigger severe MYRF‐related pathology and establishes persistent leukoencephalopathy as a novel clinical phenotype within the MYRF disease spectrum.