Background: The peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) and Nuclear factor erythroid 2-related factor 2 (Nrf2) are key regulators controlling antioxidant defense, mitochondrial biogenesis and cellular proteostasis. Dysfunction of these processes has been implicated in the pathogenesis of Parkinson’s disease (PD). Activation of PGC-1α/Nrf2 might improve mitochondrial dysfunction, promote α-synuclein (α-syn) clearance and attenuate degeneration of nigral dopaminergic neurons in PD. Methods: Neurotoxin-induced in vitro PD model, 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-treated mice model, unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA)-lesioned rat model, and transgenic mice overexpression of human A53T mutant α-synuclein were used to evaluate the neuroprotective and neurorescue effect of tetramethylpyrazine nitrone (TBN), a free radical scavenger, and its regulation on PGC-1α/Nrf2 pathway. Results: TBN protected against 1-methyl-4-phenylpyridinium (MPP + ) and 6-OHDA insult in cultured primary midbrain neurons. TBN promoted α-syn clearance by autophagy and proteasomal pathways in cell models overexpressing the human A53T mutant α-syn. In MPTP-treated mice, unilateral 6-OHDA-lesioned rats, and the α-syn transgenic mice model, TBN improved motor impairment, increased survival of nigral dopaminergic neurons, and elevated striatal dopamine levels while decreasing the products of oxidative damage. Importantly, TBN down-regulated the α-syn level in the brain and serum of α-syn-transgenic mice. These in vitro and in vivo improvements were associated with activation of the PGC-1α/Nrf2 signaling pathway, resulting in reduced oxidative stress, and enhanced mitochondrial functions. Conclusions: Our work demonstrates that TBN activates PGC-1α/Nrf2 and increases the survival of nigral dopaminergic neurons. These results suggest that TBN warrants further development as a potential new PD treatment.