Neurodegenerative disorders are characterized by a continuous neurons loss resulting in a wide range of pathogenesis affecting the motor impairment. Several strategies are outlined for therapeutics of synthetic and natural PPARs agonists in some neurological disorders; Parkinson's disease (PD), Alzheimer's disease (AD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). The aim of this review is to provide a recent update of the previously reported studies, and reviews dealing with the medicinal chemistry of PPARs and their agonists, and to highlight the outstanding advances in the development of both synthetic compounds including; PPAR alpha agonists (fibrates), PPAR gamma agonists (thiazolidindiones), and PPAR beta/delta agonists either as sole or dual acting PPAR full or pan agonists, in addition to the natural phytochemicals; acids, cannabinoids, and flavonoids for their different neuroprotection effects in the previously mentioned neurodegenerative disorders (PD, AD, MS, ALS, and HD). Moreover, this review reports the diverse pre-clinical and clinical studies of PPARs agonists in the neurodegenerative diseases via cellular, and animal models and human.