ABSTRACT Optic neuritis can be an early sign of demyelinating diseases like multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein (MOG) antibody-associated diseases (MOGAD). We investigated the presence or absence of head and spinal cord lesions on magnetic resonance imaging (MRI) and assessed whether cerebrospinal fluid (CSF) tests are useful in detecting demyelinating disease in patients with first diagnosed optic neuritis. We conducted a retrospective study of 111 patients (47 idiopathic, 19 NMOSD, 16 MOGAD, 16 MS, 6 optic neuritis with cerebral lesions but that does not meet the McDonald’s criteria for MS (ON+)), and 7 chronic relapsing inflammatory optic neuropathy) diagnosed with optic neuritis without cerebral or spinal symptoms. Patients underwent evaluations including orbital, head, and spine MRI, along with CSF analysis. Among the 111 patients, 20 (35.1%: 4 NMOSD, 4 MOGAD, 7 MS, and 6 ON+) exhibited intracerebral or spinal cord lesions. Twelve patients showed findings on both orbital and head MRI, while six had no orbital MRI findings except for optic neuritis but exhibited lesions on head MRI. Five patients had spinal lesions without intracerebral lesions. CSF analysis revealed positive oligoclonal bands and elevated myelin basic protein levels indicate the high likelihood with systemic inflammatory demyelinating diseases. Even in the absence of concomitant encephalitis or myelitis symptoms or a history of these conditions, MRI images of patients with optic neuritis sometimes reveal lesions in the brain or spinal cord. CSF abnormalities were indicative of systemic demyelinating disease presence, extending beyond MS to NMOSD and MOGAD.