Autophagy is an abnormal protein degradation and recycling process that is impaired in various neurological diseases like Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease. Spermidine is a natural polyamine found in various plant- and meat-based diets that can induce autophagy, and is decreased in various neurodegenerative diseases. It acts on epigenetic enzymes like E1A-binding protein p300, HAT enzymes like Iki3p and Sas3p, and α-tubulin acetyltransferase 1 that modulate autophagy. Histone modifications like acetylation, phosphorylation, and methylation could influence autophagy. Autophagy is epigenetically regulated in various neurodegenerative disorders with many epigenetic enzymes and miRNAs. Polyamine regulation plays an essential role in the disease pathogenesis of AD and PD. Therefore, in this review, we discuss various enzymes and miRNAs involved in the epigenetic regulation of autophagy in neurodegenerative disorders and the role of spermidine as an autophagy enhancer. The alterations in spermidine-mediated regulation of Beclin-1, LC3-II, and p62 genes in AD and other PD-associated enzymes could impact the process of autophagy in these neurodegenerative diseases. With the ever-growing data and such promising effects of spermidine in autophagy, we feel it could be a promising target in this area and worth further detailed studies.