BACKGROUND: Multiple sclerosis (MS) is one of the most severe autoimmune disorder of the central nervous system (CNS). OBJECTIVE: The present research work was aimed to formulate and investigate teriflunomide (TFM)-loaded intranasal (i.n.) nanostructured lipid carriers (NLC) for the treatment of multiple sclerosis (MS). METHODS: The TFM-loaded NLC (TFM-NLC) nanoparticles were prepared by melt emulsification ultrasonication method using biodegradable and biocompatible polymers. The Box-Behnken statistical design was applied to optimize the formulation. The optimized NLC formulation was subjected to evaluate for particle size, entrapment efficiency (%), in vitro and ex vivo permeation. The safety and efficacy of optimized formulations were demonstrated using pharmacodynamic, subacute toxicity and hepatotoxicity data. RESULTS: Experimental data demonstrated that optimized NLC formulation (F17) showed significant size (99.82 ± 1.36 nm), zeta potential (-22.29 ± 1.8 mV) and % entrapment efficiency (83.39 ± 1.24%). Alternatively, ex vivo permeation of TFM mucoadhesive NLC (TFM-MNLC) and TFM-NLC was observed 830 ± 7.6 and 651 ± 9.8 µg/cm, respectively. Whereas, TFM-MNLC shows around 2.0-folds more J than the TFM-NLC. Finally, TFM-MNLC (i.n.) formulation produced the rapid remyelination in cuprizone-treated animals and decreases the number of entries in open compartment of EPM when compared with negative control and TFM-NLC (oral) animals. Simultaneously, the nanoformulation did not reflect any gross changes in hepatic biomarkers and subacute toxicity when compared with control. CONCLUSIONS: Hence it can be inferred that the nose-to-brain delivery of TFM-MNLC can be considered as effective and safe delivery for brain disorders.