Fingolimod (Fin), an FDA-approved drug, is used to control relapsing-remitting multiple sclerosis (MS). This therapeutic agent faces crucial drawbacks like poor bioavailability rate, risk of cardiotoxicity, potent immunosuppressive effects, and high cost. Here, we aimed to assess the therapeutic efficacy of nano-formulated Fin in a mouse model of experimental autoimmune encephalomyelitis (EAE). Results showed the suitability of the present protocol in the synthesis of Fin-loaded CDX-modified chitosan (CS) nanoparticles (NPs) ([email protected]) with suitable physicochemical features. Confocal microscopy confirmed the appropriate accumulation of synthesized NPs within the brain parenchyma. Compared to the control EAE mice, INF-γ levels were significantly reduced in the group that received [email protected] (p < 0.05). Along with these data, [email protected] reduced the expression of TBX21, GATA3, FOXP3, and Rorc associated with the auto-reactivation of T cells (p < 0.05). Histological examination indicated a low-rate lymphocyte infiltration into the spinal cord parenchyma after the administration of [email protected] Of note, HPLC data revealed that the concentration of nano-formulated Fin was about 15-fold less than Fin therapeutic doses (TD) with similar reparative effects. Neurological scores were similar in both groups that received nano-formulated fingolimod 1/15th of free Fin therapeutic amounts. Fluorescence imaging indicated that macrophages and especially microglia can efficiently uptake [email protected] NPs, leading to the regulation of pro-inflammatory responses. Taken together, current results indicated that CDX-modified CS NPs provide a suitable platform not only for the efficient reduction of Fin TD but also these NPs can target the brain immune cells during neurodegenerative disorders.