A 2‐year‐old female cat was referred for progressive neurological signs indicative of involvement of the prosencephalon, cerebellum, and brainstem. Magnetic resonance imaging identified multifocal, bilateral, symmetrical lesions with strong contrast enhancement, affecting multiple areas of the brain. Neuropathology at necropsy showed demyelination, necrotic lesions, spongiosis, and neuropil edema with reactive astrogliosis and neovascularization. Ultrastructural study indicated mitochondrial polymorphism. Genetic investigations outlined 2 polymorphisms within the tRNA‐Leu(UUR) gene of mitochondrial DNA. Imaging and neuropathological findings were consistent with selective symmetrical necrotizing encephalopathy, for which genetic investigations support mitochondrial pathogenesis.