Optic neuritis (ON) is a common manifestation of multiple sclerosis (MS). Aiming to evaluate the retinal nerve fiber layer (RNFL) with optical coherence tomography (OCT), patients with relapsing-remitting (RR) MS experiencing ON were consecutively enrolled. RNFL, ganglion cell layer (GCL), foveal thickness, and macular volume were evaluated in both the ON and unaffected (nON) eye within six days from the relapse onset (T0) and after six months (T1). Ninety patients were enrolled. At T0, ON eyes showed a significantly increased RNFL when compared to the nON eyes (129.1 ± 19.5 vs. 100.5 ± 10.1, < 0.001). At T1 versus T0, the ON eyes showed a thinner RNFL (129.1 ± 19.5 vs. 91.6 ± 20.2, < 0.001) and a significantly decreased GCL (80.4 ± 8.8 vs. 73.8 ± 11.6; < 0.005). No differences were found in the nON group in retinal parameters between T0 and T1. A multivariate logistic regression analysis showed that a higher number of relapses (not ON) and a greater swelling of RNFL at T0 were associated with poor recovery. The assessment of RNFL through OCT during and after ON could be used to predict persistent visual disability.