Repressor element-1 silencing transcription factor (REST) is a transcriptional repressor involved in neurodevelopment and neuroprotection that forms a complex with the REST corepressor 1 (CoREST1), CoREST2 and CoREST3 (encoded by RCOR1, RCOR2 and RCOR3, respectively). Emerging evidence suggests the CoREST family have the ability to target unique genes, in a REST-independent manner, in various neural and glial cell types at different stages of development. There is limited knowledge on expression and function of CoREST3 in neurodevelopment and neurodegeneration. This study used 2D and 3D human pluripotent stem cell models to define gene expression pattern and function in human neuronal differentiation. This work also utilised rat brain tissue to define changes in the aging brain and human post-mortem tissue from Alzheimer’s disease patients to investigate the changes of CoREST3 in neurodegeneration. The findings demonstrate the dynamic expression pattern of CoREST3 in neuronal maturation, aging and neurodegeneration. Furthermore, this work has identified a potential role for CoREST3 in regulating neuronal differentiation and the expression of the epigenetic regulator HDAC2. Overall, these novel findings are significant in deepening our understanding of how key transcription factors govern the molecular mechanisms involved in neurodevelopment and neuronal function.