Primary eye diseases, particularly those affecting the optic nerve and retina, may closely mimic multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), or other autoimmune demyelinating conditions. This chapter provides a comprehensive review of key ophthalmologic conditions that may present as MS mimics, including chronic relapsing inflammatory optic neuropathy (CRION), Leber hereditary optic neuropathy (LHON), neuroretinitis, non-arteritic anterior ischemic optic neuropathy (NAION), retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S), trochleitis, and uveitis. For each disease, we detail the clinical features, diagnostic criteria, neuroimaging findings, laboratory markers, and course. Conditions such as CRION and MOGAD-associated optic neuritis exhibit corticosteroid responsiveness and recurrence, whereas LHON often results in painless, irreversible bilateral visual loss with mitochondrial inheritance. Neuroretinitis presents with a macular star pattern on fundus exam and often has infectious or inflammatory etiology. NAION is a vascular optic neuropathy characterized by acute, painless visual loss and optic disc swelling, often in older patients with vascular risk factors. RVCL-S, a rare genetic vasculopathy, may feature systemic and cerebral involvement with tumor-like lesions, contrast enhancement, and retinal microinfarcts. Trochleitis presents with localized trochlear pain and mimics headache syndromes. Uveitis, particularly intermediate and posterior forms, can be associated with MS and may even precede its neurological onset. A careful ophthalmologic evaluation—including optical coherence tomography (OCT), visual evoked potentials (VEP), fluorescein angiography, and MRI—is often essential to avoid misdiagnosis and inappropriate immunotherapy. Understanding the unique features and red flags of these disorders helps clinicians accurately distinguish them from true demyelinating diseases and tailor management appropriately. This chapter provides practical diagnostic and therapeutic guidance for neurologists and ophthalmologists facing complex visual presentations.