Optic neuritis is the most common cause of unilateral visual loss associated with orbital pain on ocular movements and impaired colour vision. It can present with anterior optic neuritis, papillitis, a swollen optic disc, retrobulbar neuritis with a normal optic disc, neuritis with oedema of the optic disc and the macular star or anterior ischemic neuropathy. It may be the only manifestation of a disease such as demyelination or associated with systemic diseases such as systemic lupus, giant cell arteritis, Sjogren’s syndrome, herpes simplex, herpes zoster, Lyme disease, CMV, EBV, HIV, toxoplasmosis, West Nile virus, Chikungunya, dengue fever, Rift Valley fever, mumps, rubella, measles, cat scratch disease, tuberculosis, syphilis, rickettsia illnesses, Q fever, Whipple disease, brucellosis, leptospirosis, leprosy, toxocariasis, malaria, Cryptococcus, candidiasis, histoplasmosis, Aspergillosis, mucormycosis, Bacillus Chalmette-Guerin (BCG) vaccination, ethanol and methanol toxicity, sarcoidosis, neuromyelitis optica and Liber’s hereditary optic neuropathy. A systemic approach to the diagnosis is of paramount importance in confirming, diagnosing and treating optic neuritis and underlying systemic diseases to provide definitive cures. Failure to diagnose optic neuritis and treat the cause may result in optic atrophy and permanent blindness. In this paper, we reviewed the diagnosis and differential diagnoses of optic neuritis, including arteritis, ischemic, neuroretina, and vasculitic causes.