COE transcription factors are conserved across divergent animals and are important for development. COE genes are also functional in adult animals and have been implicated in central nervous system (CNS) diseases; however, the function of COE in the adult CNS remains poorly understood. Planarian regeneration provides an excellent model to study the function of transcription factors in cell differentiation and in mature cells. In planarians, coe is expressed in differentiating and mature neurons, and its function is required for CNS regeneration. In this study, we show that coe is required to maintain structure and function of the CNS in uninjured planarians. We took advantage of this phenotype to identify genes regulated by coe by comparing global gene expression changes between control and coe mRNA-deficient planarians. This approach revealed downregulated genes downstream of coe with biological roles in CNS function. Expression analysis of the downregulated genes uncovered previously unknown candidate targets of coe in the CNS. Furthermore, functional analysis of downstream targets identified coe-regulated genes required for CNS repair. These results demonstrate that the roles of COE in stem cell specification and neuronal function are active and indispensable during CNS maintenance in adult animals.