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Specific red flag clinical signs in ophthalmology might indicate serious underlying systemic disease. This review illustrates five big red flags in neuro-ophthalmology of interest to comprehensive ophthalmologists. These clinical signs include: (i) retinochoroidal venous collaterals, (ii) optic disc edema with a macular star, (iii) chronic red eyes refractory to topical therapy, (iv) aberrant regeneration not secondary to ischemia, and (v) the misdiagnosis of immune disease in immunosuppressed patients. We also describe the common causative factors suggested by these red flags (i.e., optic nerve sheath meningioma, infectious neuroretinitis, carotid cavernous fistula, compressive third nerve lesions, and the incorrect diagnosis of Tolosa–Hunt syndrome [THS]), as well as the distinctive laboratory or radiographic signs for each condition.