Recent studies have shown that white matter lesions play an important role in the pathogenesis of schizophrenia. DHF-6 is a novel flavanone derivative synthesized in our laboratory. The purpose of the present study was to investigate the effects of DHF-6 on behavioral changes and white matter pathology in a 0.2% cuprizone-fed C57BL/6 mice model. The results showed that cuprizone induced a decrease in spontaneous alternations in the Y-maze test, an increase in locomotor activity in the open field test, demyelination determined by electron microscopy, a decline in the expression of myelin basic protein (MBP), a decrease in the differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (OLs), and an activation of microglia and astrocytes in the corpus callosum measured by western blot and/or immunocytochemical analyses. Intragastric administration of DHF-6 (25 and 50 mg/kg) for 5-weeks increased the spontaneous alternations, reduced locomotor activity, reversed demyelination and MBP decrease, promoted OPCs differentiation into mature OLs, and inhibited the activation of microglia and astrocytes. These results suggest that DHF-6 may improve cognitive impairment and the positive symptoms of schizophrenia by alleviating white matter lesions via facilitating remyelination and inhibiting neuroinflammation, thus may be beneficial in the treatment of schizophrenia.