The ubiquitin-proteasome system (UPS) is a crucial cellular mechanism primarily responsible for breaking down most misfolded or defective proteins within cells. The two primary parts of the UPS are the proteasome, which breaks down proteins, and the ubiquitination system, which marks proteins for destruction. The UPS comprises essential elements such as enzymes that aid in the binding of ubiquitin (Ub) to specific proteins, as well as those that eliminate Ub and degrade Ub chains. E1 ubiquitin-activating enzymes, E2 ubiquitin-conjugating enzymes, and E3 ubiquitin ligases all play a part in the process of conjugating Ub to a target protein. Numerous illnesses, such as cancer, cardiovascular disease, ailments of the immune system, and neurodegenerative disorders (NDDs), have been linked to UPS dysregulation. Deubiquitination, mediated by deubiquitinating enzymes (DUBs), is a reversible process that carries out ubiquitination, a critical process for protein regulation. Through their ability to remove ubiquitin from protein conjugates and proofread them, DUBs are essential for controlling the UPS. Their importance goes beyond preserving neuronal processes to include modulating the course of different neurodegenerative illnesses. A characteristic shared by a number of age-related NDDs, including multiple sclerosis, Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease, and amyotrophic lateral sclerosis, is the aberrant accumulation of neurotoxic proteins. Neuronal function and cellular balance in the brain are disrupted by proteins such as amyloid-beta, Tau in AD, and α-synuclein, which is involved in PD, affecting millions of people globally. UPS plays a vital role in removing the harmful proteins, which is essential; however, the malfunction of UPS leads to the development of neurodegenerative illnesses. The various triggers that influence the UPS in neurodegenerative diseases include inflammation, oxidative stress, protein aggregation, synaptic dysfunction, and genetic mutations. The various signaling factors associated with UPS are NF-κB, PI3K/Akt/mTOR, p53, Wnt/β-catenin, c-Jun terminal kinase, and autophagy, and dysregulation of any one of the multiple signaling factors may lead to illness. It is still unclear how ubiquitination and proteasomal degradation are regulated in both normal brain function and neurodegenerative diseases, despite the fact that research on UPS-mediated protein degradation has been extensively studied. There are various physiological or pathological circumstances in which the regulation of polyubiquitination may vary. This book chapter emphasizes the triggers of UPS and its dysregulation that may lead to various neurodegenerative diseases. Also, a deeper comprehension of protein degradation processes and addressing the UPS-related problems may help in developing novel approaches for treating neurodegenerative diseases.