Oxidative stress is recognized to have a central role in the initiation and progression of Parkinson's disease (PD). Within the brain, neurons are particularly sensitive to oxidation due in part to their weak intrinsic antioxidant defense. Theoretically, neurons mostly depend on neighboring astrocytes to provide antioxidant protection by supplying cysteine-containing products for glutathione (GSH) synthesis. Astrocytes and neurons possess several amino acid transport systems for GSH and its precursors. Indeed, GSH is the most abundant intrinsic antioxidant in the central nervous system. The GSH depletion and/or alterations in its metabolism in the brain contribute to the pathogenesis of PD. Noteworthy, polyphenols possess potent antioxidant activity and can augment the GSH redox system. Numerous in vitro and in vivo studies have indicated that polyphenols exhibit potent neuroprotective effects in PD. Epidemiological studies have found an association between the consumption of dietary polyphenols and a lower PD risk. In this review, we summarize current knowledge on the biosynthesis and metabolism of GSH in the brain, with an emphasis on their contribution and therapeutic potential in PD. In particular, we focus on polyphenols that can increase brain GSH levels against PD. Furthermore, some current challenges and future perspectives for polyphenol-based therapies are also discussed.