Neuromyelitis optica is a neurotropic autoimmune inflammatory disease of the central nervous system traditionally thought to exclusively involve the optic nerves and spinal cord. With the discovery of the disease-specific aquaporin-4 antibody and the increasing recognition of clinical and characteristic imaging patterns of brain involvement in what is now termed neuromyelitis optica spectrum disorder (NMOSD), MRI now plays a greater role in diagnosis of NMOSD based on the 2015 consensus criteria and in distinguishing it from other inflammatory disorders, particularly multiple sclerosis (MS). Several brain lesion patterns are highly suggestive of NMOSD, whereas others may serve as red flags. Specifically, long corticospinal lesions, hemispheric cerebral white matter lesions and periependymal lesions in the diencephalon, dorsal brainstem and white matter adjacent to lateral ventricles are typical of NMOSD. In contrast, juxtacortical, cortical, or lesions perpendicularly oriented to the surface of the lateral ventricle suggests MS as the diagnosis. Ultimately, a strong recognition of the spectrum of MRI brain findings in NMOSD is essential for accurate diagnosis, and particularly in differentiating from MS. This pictorial review highlights the spectrum of characteristic brain lesion patterns that may be seen in NMOSD and further delineates findings that may help distinguish it from MS.