The transcription factors c-Myc and FoxO3a play significant roles in neurodegenerative processes, yet their interaction in neurological disorders remains largely unexplored. In contrast, much of the available information about their relationship comes from cancer research. While it is well-established that FoxO3a inhibits c-Myc activity, this interaction represents only a basic understanding of a far more complex dynamic, which includes exceptions under specific conditions and the involvement of additional regulatory factors. Given the critical need to address this gap for the treatment and prevention of neurodegenerative disorders, this review consolidates current knowledge on the joint roles of these two factors in neuropathology. It also highlights their conformational flexibility, post-translational modifications, and outlines potential directions for future research.