Proteostasis or protein homeostasis is the regular cellular procedure that regulates protein synthesis and protein degradation to maintain the cellular protein concentration. The process confirms the suitable folding or unfolding or refolding, and degradation of newly synthesized proteins. Different cellular proteins are continuously involved in cell development, differentiation, and aging. Maintenance of proteostasis is a very significant process in neurons (non-proliferative cells). Its failure or disturbance leads to many neurodegenerative diseases like Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) disease. Misfolded proteins are generally refolded by chaperones, but if it fails, they are targeted to proteolytic pathways. This process is completed by two main catabolic pathways, i.e., ubiquitin proteasomal degradation and autophagy to clear the misfolded proteins from the cellular environment. The ubiquitin proteasomal degradation system (UPS) targets the majority of intracellular proteins which are essential for normal cellular functions when protein is misfolded, and autophagy is one of the major intracellular machineries that eliminate misfolded proteins and maintain proteostasis. Impaired autophagy or disturbances in proteostasis are the key contributors that lead to the aggregations of unfolded or misfolded proteins such as amyloid beta and tau. This dysfunction has been a matter of concern in the pathogenesis of neurodegenerative diseases. In this chapter, we will focus on the regulation between proteostasis and autophagy and their impact on neurodegeneration.