An evolutionarily conserved ubiquitin-proteasome system (UPS) plays important roles in maintaining cellular protein homeostasis via ubiquitylation-mediated targeted degradation by the 26S proteasome. Impaired UPS (or 26S proteasomal degradation) leads to an aberrant accumulation/aggregation of proteins, which is associated with neurodegenerative disorders. Further, the processes such as neuroinflammation, oxidative damage and apoptosis also contribute to the neurodegenerative diseases. UPS/proteasome has crucial functions in regulating inflammation, oxidative stress and apoptosis, and hence neurodegenerative disorders. Therefore, the compounds that can modulate the UPS/proteasome activity with anti-inflammatory, anti-oxidative and anti-apoptotic responses would elicit neuroprotective functions against neurodegenerative diseases. A number of synthetic inhibitors have been developed to regulate UPS/proteasome, some of which are clinically approved, while others are in trial. However, these inhibitors have severe side effects. Thus, studies over the years garnered attention into the natural products that can modulate UPS/proteasome and have anti-inflammatory, anti-oxidative and anti-apoptotic and other beneficial roles for neuroprotection. Here, we describe the roles of a set of natural products involved in the regulation of UPS/proteasome with neuroprotective functions and therapeutic potentials for neurodegenerative diseases.