The brain is rich in fatty acids (FAs), with polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (C22:6n-3, DHA) and arachidonic acid (C20:4n-6, ARA), and the former predominantly stored in the form of phosphatidylcholine, phosphatidyl ethanolamine (PE, diacyl and plasma phospholipid proform), and phosphatidylserine (PS), while the latter is mainly found in ethanolamine phosphoglycerides (EPG) and contributes to constitute most of phosphoglycerides. When required by the body, PUFAs are liberated from membrane phospholipids (either directly or via their metabolites, which are generated by a series of enzymatic reactions) to participate in various cerebral physiological processes. PUFAs and their derivatives play crucial roles in modulating numerous bodily functions, including neuronal signal transmission, neurogenesis, neuroinflammation, and glucose uptake in the brain, thereby sustaining fundamental brain function. Although PUFAs have been implicated in a spectrum of neurological disorders, including acute brain injury (TBI), multiple sclerosis (MS), and neurodegenerative diseases, their role in conditions such as depression, Alzheimer's disease (AD), and Parkinson's disease (PD) is particularly noteworthy. These disorders are closely linked to critical brain functions, including cognition, memory, and inflammatory processes. Given the substantial body of research elucidating the involvement of PUFAs in the pathogenesis and progression of these diseases, this review will specifically concentrate on their impact within these contexts.