The supportive functions of oligodendrocytes are required for the survival and development of axons, ensuring the organization of highly specialized neuronal networks in brain. Although the molecules that regulate oligodendrocyte differentiation in vitro have been identified, their roles in vivo are largely uncertain. Here we report that fyn deficiency on the C57BL/6 genetic background resulted in premature death, showing severe hydrocephalus with neonatal onset. One week after birth, fyn-deficient mice showed enlarged lateral ventricles with thinner cerebral cortices and degenerating axons in the corpus callosum. In addition, before the onset of myelination, the number of oligodendrocytes was reduced and their morphogenesis was impaired in the cerebral cortex. These results demonstrate that Fyn is essential for normal brain development and suggest that defects in oligodendrocyte development cause degeneration of cortical axons and subsequent hydrocephalus in fyn-deficient mice.