Multiple sclerosis (MS) is a common neurological disease affecting the optic nerve, directly or indirectly, through transsynaptic axonal degeneration along the visual pathway. New ophthalmological tools, arguably the most important being optical coherence tomography (OCT), could prove paramount in redefining MS diagnoses and shaping their follow-up protocols, even when the optic nerve is not involved. A prospective clinical study was conducted. In total, 158 eyes from patients previously diagnosed with relapsing remitting MS (RRMS)-with or without optic neuritis (ON), clinically isolated syndrome (CIS) with or without ON, and healthy controls were included. Each patient underwent an ophthalmologic exam and OCT evaluation for both eyes (a posterior pole analysis (PPA) and the optic nerve head radial circle protocol (ONH-RC)). The macular retinal thickness (the 4 × 4, respectively, 2 × 2 grid) and thickness of the peripapillary retinal nerve fiber layer (pRNFL) were investigated. Various layers of the retina were also compared. Our study observed significant pRNFL thinning in the RRMS eyes compared to the control group, the pRNFL atrophy being more severe in the RRMS-ON eyes than the RRMS-NON eyes. In the ON group, the macular analysis showed statistically significant changes in the RRMS-ON eyes when compared only to the CIS-ON eyes, regarding decreases in the inner plexiform layer (IPL) thickness and inner nuclear layer (INL) on the central 2 × 2 macular grid. The neurodegenerative process affected both the inner retina and pRNFL, with clinical damage appearing for the latter in the following order: CIS-NON, CIS-ON, RRMS-NON, and RRMS-ON. In the presence of optic neuritis, SMRR patients presented an increase in their outer retina thickness compared to CIS patients. To differentiate the MS patients from the CIS patients, in the absence of optic neuritis, OCT Posterior Pole Analysis could be a useful tool when using a central 2 × 2 sectors macular grid. Retinal changes in MS seem to start from the fovea and spread to the posterior pole. Finally, MS could lead to alterations in both the inner and outer retina, along with pRNFL.