Cuprizone (CPZ), a copper chelator that has been shown to selectively damage white matter, can induce a novel animal model to mimic some symptoms of schizophrenia. This study aimed to examine the effect of clozapine (CLZ) on behavioural changes induced by CPZ exposure and try to explore the underlying mechanisms. Behavioural abnormalities associated with feeding mice a 0.4% (w/w) CPZ-containing diet were assessed by Y-maze, spontaneous locomotor activity, and climbing tests. CLZ treatment reversed the increase in total explored distance, exploring velocity, locomotor movements, climbing behaviours and glial activation induced by CPZ exposure. Our findings indicate that increased glial activation may be related to behavioural abnormalities in CPZ exposure mice and that anti-inflammatory properties may be involved in the CLZ mechanisms. CPZ short-term exposure with a higher dosage may offer a useful model to study some aspects of schizophrenia and evaluate the efficacy of antipsychotics.