The ubiquitin-proteasome system (UPS) is vital for maintaining protein quality control and cellular homeostasis by degrading various abnormal proteins such as short-lived, misfolded, mislocated, mutant, and damaged proteins. The dysregulation in the functioning of the UPS results in the buildup of abnormal protein aggregates, contributing to cellular dysfunction and death. This malfunction of UPS is closely linked to the progression of many neurodegenerative diseases, including Alzheimer’s disease, where the inability of UPS to remove these toxic proteins plays a key role. This chapter explores the fundamental role of the UPS in neuronal function and its implication in neurodegenerative diseases. The current therapeutic modalities have failed to address the root cause of neurodegeneration to stop or delay the development of the disease. Thus, this chapter also discusses the neuroprotective roles of the UPS and the potential therapeutic strategies targeting to enhance UPS function in treating neurodegenerative diseases. Therapeutic strategy, such as targeted protein degradation through proteolysis targeting chimeras (PROTACs), represents a promising new therapeutic approach for tackling disease-causing proteins that are challenging to target with traditional small molecules.