Feeding cuprizone (CPZ) to mice causes demyelination and reactive gliosis in the central nervous system (CNS), hallmarks of some neurodegenerative diseases like multiple sclerosis. However, relatively little is known regarding the behavioural deficits associated with CPZ-feeding and much of what is known is contradictory. This study investigated whether 37 days oral feeding of 0.2% CPZ to young adult mice evoked sensorimotor behavioural changes. Behavioural tests included measurements of nociceptive withdrawal reflex responses and locomotor tests. Additionally, these were compared to histological analysis of the relevant CNS regions by analysis of neuronal and glial cell components. CPZ-fed mice exhibited more foot slips in walking ladder and beam tests compared to controls. In contrast, no changes in nociceptive thresholds to thermal or mechanical stimuli occurred between groups. Histological analysis showed demyelination throughout the CNS, which was most prominent in white matter tracts in the cerebrum but was also elevated in areas such as the hippocampus, basal ganglia and diencephalon. Profound demyelination and gliosis was seen in the deep cerebellar nuclei and brain stem regions associated with the vestibular system. However, in the spinal cord changes were minimal. No loss of oligodendrocytes, neurons or motoneurons occurred but a significant increase in astrocyte staining ensued throughout the white matter of the spinal cord. The results suggest that CPZ differentially affects oligodendrocytes throughout the CNS and induces subtle motor changes such as ataxia. This is associated with deficits in CNS regions associated with motor and balance functions such as the cerebellum and brain stem.