No effective treatments have been established to delay or prevent the progression of multiple system atrophy (MSA), which is characterised by the accumulation of abnormal α-synuclein (α-Syn) species, including toxic α-Syn oligomers, in the central nervous system. In our previous study, we demonstrated that intranasal administration of trehalose reduces the levels of α-Syn oligomer by accelerating their conversion from toxic α-Syn oligomers to less harmful fibrils in a human α-Syn inducible MSA mouse model. This finding suggests that reducing α-Syn oligomers may be a crucial therapeutic strategy for MSA. The present study aimed to assess the potential of intranasal ergothioneine (ERG) administration in ameliorating MSA pathology within the MSA mouse model. A cognitive function test and electrophysiological analysis revealed that ERG administration significantly improved short-term spatial memory associated with hippocampal activity, with performance nearing normal levels. Immunohistochemical analysis showed that ERG treatment increased human α-Syn-positive areas within the dentate gyrus + dentate hilus regions of the hippocampus. By contrast, ERG treatment also led to a reduction in α-Syn phosphorylation in the cerebral cortex. Furthermore, immunoblotting confirmed that ERG treatment elevated expression levels of α-Syn monomer, while significantly reducing α-Syn dimer levels in the ERG-treated MSA model mice compared with untreated counterparts. Thus, the modification of α-Syn induced by ERG treatment may result in a reduction of α-Syn oligomers. Here, we demonstrate that intranasal administration of ERG improved short-term spatial memory in the MSA mouse model.