Sirtuin-3 (SIRT3) is a NAD⁺-dependent protein deacetylase that is located in mitochondria, regulating mitochondrial proteins and maintaining cellular antioxidant status. Increasing evidence demonstrates that SIRT3 plays a role in degenerative disorders including Parkinson’s disease (PD), which is a devastating nervous system disease currently with no effective treatments available. Although the etiology of PD is still largely ambiguous, substantial evidence indicates that mitochondrial dysfunction and oxidative stress play major roles in the pathogenesis of PD. The imbalance of reactive oxygen species (ROS) production and detoxification leads to oxidative stress that can accelerate the progression of PD. By causing conformational changes in the deacetylated proteins SIRT3 modulates the activities and biological functions of a variety of proteins involved in mitochondrial antioxidant defense and various mitochondrial functions. Increasingly more studies have suggested that upregulation of SIRT3 confers beneficial effect on neuroprotection in various PD models. This review discusses the mechanism by which SIRT3 regulates intracellular oxidative status and mitochondrial function with an emphasis in discussing in detail the regulation of SIRT3 on each component of the five complexes of the mitochondrial respiratory chain and mitochondrial antioxidant defense, as well as the pharmacological regulation of SIRT3 in light of therapeutic strategies for PD.