Millions of people are affected by neuronal disorders that are emerging as a principal cause of death after cancer. Alzheimer’s disease, ataxia, Parkinson’s disease, multiple system atrophy, and autism comprise the most common ones, being accompanied by loss of cognitive power, impaired balance, and movement. In past decades, natural polyphenols obtained from different sources including bacteria, fungi, and plants have been utilized in the traditional system of medicine for the treatment of several ailments. Endophytes are one such natural producer of secondary metabolites, namely, polyphenols, which exhibit strong abilities to assist in the management of such affections, through modifying multiple therapeutic targets and weaken their complex physiology. Limited research has been conducted in detail on bioactive compounds present in the endophytic fungi and their neuroprotective effects. Therefore, this review aims to provide an update on scientific evidences related to the pharmacological and clinical potential along with proposed molecular mechanism of action of endophytes for neuronal protection.