Proteostasis involves processes that are fundamental for neural viability. Thus, protein misfolding and the formation of toxic aggregates at neural level, secondary to dysregulation of the conservative mechanisms of proteostasis, are associated with several neuropsychiatric conditions. It has been observed that impaired mitochondrial function due to a dysregulated proteostasis control system, that is, ubiquitin-proteasome system and chaperones, could also have effects on neurodegenerative disorders. We aimed to critically analyze the available findings regarding the neurobiological implications of proteostasis on the development of neurodegenerative and psychiatric diseases, considering the mitochondrial role. Proteostasis alterations in the prefrontal cortex implicate proteome instability and accumulation of misfolded proteins. Altered mitochondrial dynamics, especially in proteostasis processes, could impede the normal compensatory mechanisms against cell damage. Thereby, altered mitochondrial functions on regulatory modulation of dendritic development, neuroinflammation, and respiratory function may underlie the development of some psychiatric conditions, such as schizophrenia, being influenced by a genetic background. It is expected that with the increasing evidence about proteostasis in neuropsychiatric disorders, new therapeutic alternatives will emerge.