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Dietary fibers are a major source of short-chain fatty acids (SCFAs) in the body, and the fermentation products of SCFAs induced by intestinal microbiota affect energy metabolism. Apart from serving as an energy source in the intestines, SCFAs also inhibit autophagy, nucleotide-binding oligomerization domain-containing protein, LRR, and pyrin domain-containing protein 3 inflammasome. SCFAs provide numerous therapeutic benefits through their influence on cognitive functioning and neurodegenerative diseases (NDD) pathophysiology. Additionally, NDDs are associated with abnormalities in the gut microbiota, including an increased load of pathogens and opportunistic microbes. SCFAs maintain the healthy mitochondrial function and stimulate the maturation of microglia, which consequently suppresses the progression of NDD and cognitive decline by regulating inflammation and oxidative stress. Basically, SCFAs function as cofactors for the host's mitochondrial enzymes and are being studied for their ability to reverse the alteration in the gut microbiota seen in many NDDs and cardiac diseases. In the present review, the focus is on the detrimental and beneficial roles of SCFAs in NDD, emphasizing the effects of SCFA on following phenomenon: (1) alteration in gut microbiota profile associated with NDD, (2) the molecular mechanism of metabolic regulation by SCFA's, and its co-relation with NDD, (3) use of mitochondrial antioxidants as a strategy for maintaining microbiota diversity in the gut, and (4) the future direction of metabolism and neurodegeneration in the gut–brain axis. In addition, the interplay between gut microbiota, SCFAs, epithelial barrier, and neuroimmune signaling in neurodegeneration has been reviewed. The current systematic review and meta-analysis indicate that dietary fermentation of nondigestible fibers leads to the production of short chain fatty acids (SCFAs) by gut microbiota. Moreover, they directly act on the central nervous system and inhibit the progression of different neurodegenerative diseases such as Parkinson disease, Alzheimer disease, and multiple sclerosis. SCFAs act by triggering cellular antioxidants and inhibiting inflammation. The properties of SCFAs depend on the G protein–coupled receptors, histone deacetylases and peroxisome proliferator-activated receptor gamma, and regulatory T-cell activation. [Display omitted] [ABSTRACT FROM AUTHOR]