The neural basis of abnormal social behavior in autism spectrum disorder (ASD) remains incompletely understood and previous studies has highlighted that altered myelination could be involved in the pathophysiology of ASD. We have characterized the myelination process during development in the cntnap2-/- mouse model of ASD. We observed that oligodendrocyte differentiation and myelination are transiently impaired during cortical development in cntnap2-/- mice. Thus, we observed a reduction in myelinated fibers, the number of nodes of Ranvier and the proportion of mature oligodendrocytes in somatosensory cortex and corpus callosum in young mice. Moreover, we detected an increase in the number of Caspase-3+ oligodendrocytes, most of them in microglia phagocytic pouches, suggesting oligodendroglial survival is affected during development. Although myelination is nearly restored in adult mice, a more detailed analysis of the column pattern of myelination revealed an altered organization or orientation of myelinated fibers. As myelination could be essential for circuit development, we hypothesized that restoring OL differentiation or promoting myelination during the brain plasticity window could partially reverse neurodevelopmental abnormalities as well as cognitive and social behaviour disturbances in ASD. Clemastine, a histamine H1 antagonist with anticholinergic properties against muscarinic M1 receptor, has promyelinating properties and Pranlukast, an antagonist of the orphan receptor GPR17, promotes oligodendrocyte differentiation and myelination. Treatment with both drugs during development restored myelin deficits and rescued social deficits and behavioural inflexibility in cntnap2-/- mice. Our findings corroborate that myelin deficits are associated to ASD and that promoting myelination could be a therapeutic target in this disorder.