Multiple sclerosis (MS) is a neurodegenerative disease characterised by inflammation and damage to the myelin sheath, resulting in physical and cognitive disability. Recent evidence suggests that activating kappa opioid receptors (KOR) has a beneficial effect on the progression of MS. Although many KOR agonists are not suitable for clinical use, nalfurafine is a potent, clinically used KOR agonist with a favourable side-effect profile. Using the experimental autoimmune encephalomyelitis (EAE) model, the effect of therapeutically administered nalfurafine or U50,488 on remyelination, CNS infiltration, and peripheral immune responses were compared. Nalfurafine promoted recovery and remyelination during EAE. Additionally, nalfurafine was more effective than U50,488 and promoted disease reduction when administered following chronic demyelination. KOR antagonism with nor-BNI impaired full recovery by nalfurafine, suggesting that nalfurafine may mediate recovery from EAE in a KOR-dependent fashion. Furthermore, nalfurafine treatment reduced CNS infiltration (especially CD4+ and CD8+ T cells) and promoted an immunoregulatory environment by decreasing the Th17 response. Finally, nalfurafine promoted remyelination in the cuprizone demyelination model, supporting the direct effect on remyelination in the absence of peripheral immune cell invasion. Overall, our findings support the potential of nalfurafine to promote recovery and remyelination and highlight its promise for clinical use in MS.