<b><i>Introduction:</i></b> We aimed to develop and validate an Expanded Disability Status Scale (EDSS) model through clinical, optical coherence tomography (OCT), and magnetic resonance imaging (MRI) measures. <b><i>Methods:</i></b> Sixty-four multiple sclerosis (MS) patients underwent peripapillary retinal nerve fiber layer and segmented macular layers evaluation through OCT (Spectralis, Heidelberg Engineering). Brain parenchymal fraction was quantified through Freesurfer, while cervical spinal cord (SC) volume was assessed manually guided by Spinal Cord Toolbox software analysis. EDSS, neuroradiological, and OCT assessment were carried out within 3 months. OCT parameters were calculated as the average of both nonoptic neuritis (ON) eyes, and in case the patient had previous ON, the value of the fellow non-ON eye was taken. Brain lesion volume, sex, age, disease duration, and history of disease-modifying treatment (1st or 2nd line disease-modifying treatments) were tested as covariables of the EDSS score. <b><i>Results:</i></b> EDSS values correlated with patient’s age (<i>r</i> = 0.543, <i>p</i> = 0.001), SC volume (<i>r</i> = −0.301, <i>p</i> = 0.034), and ganglion cell layer (GCL, <i>r</i> = −0.354, <i>p</i> = 0.012). Using these correlations, an ordinal regression model to express probability of diverse EDSS scores were designed, the highest of which was the most probable (Nagelkerke <i>R</i>² = 43.3%). Using EDSS cutoff point of 4.0 in a dichotomous model, compared to a cutoff of 2.0, permits the inclusion of GCL as a disability predictor, in addition to age and SC. <b><i>Conclusions:</i></b> MS disability measured through EDSS is an age-dependent magnitude that is partly conditioned by SC and GCL. Further studies assessing paraclinical disability predictors are needed.