Cockayne syndrome (CS) is a rare genetic neurodevelopmental disorder, characterized by a deficiency in transcription-coupled subpathway of nucleotide excision DNA repair (TC-NER). Mutation of the Cockayne syndrome B (CSB) gene affects basal transcription, which is considered a major cause of CS neurologic dysfunction. Here, we generate a rat model by mimicking a nonsense mutation in the CSB gene. In contrast to that of the Csb-/- mouse models, the brains of the CSB-deficient rats are more profoundly affected. The cerebellar cortex shows significant atrophy and dysmyelination. Aberrant foliation of the cerebellum and deformed hippocampus are visible. The white matter displays high glial fibrillary acidic protein (GFAP) staining indicative of reactive astrogliosis. RNA sequencing (RNA-seq) analysis reveals that CSB deficiency affects the expression of hundreds of genes, many of which are neuronal genes, suggesting that transcription dysregulation could contribute to the neurologic disease seen in the CSB rat models.