Neurodegenerative diseases, characterized by a progressive loss of brain function, affect the lives of millions of individuals worldwide. The complexity of the brain poses a challenge for scientists trying to map the biochemical and physiological pathways to identify areas of pathological errors. Brain samples of patients with neurodegenerative diseases have been shown to contain large amounts of misfolded and abnormally aggregated proteins, resulting in dysfunction in certain brain centers. Removal of these abnormal molecules is essential in maintaining protein homeostasis and overall neuronal health. Macroautophagy is a major route by which cells achieve this. Administration of certain autophagy-enhancing compounds has been shown to provide therapeutic effects for individuals with neurodegenerative conditions. SQSTM1/p62 is a scaffold protein closely involved in the macroautophagy process. p62 functions to anchor the ubiquitinated proteins to the autophagosome membrane, promoting degradation of unwanted molecules. Modulators targeting p62 to induce autophagy and promote its protective pathways for aggregate protein clearance have high potential in the treatment of these conditions. Additionally, causal relationships have been found between errors in regulation of SQSTM1/p62 and the development of a variety of neurodegenerative disorders, including Alzheimer’s, Parkinson’s, Huntington’s, amyotrophic lateral sclerosis, and frontotemporal lobar degeneration. Furthermore, SQSTM1/p62 also serves as a signaling hub for multiple pathways associated with neurodegeneration, providing a potential therapeutic target in the treatment of neurodegenerative diseases. However, rational design of a p62-oriented autophagy modulator that can balance the negative and positive functions of multiple domains in p62 requires further efforts in the exploration of the protein structure and pathological basis.