Parkinson’s disease (PD) is the second most common neurodegenerative disease. Although the etiology of PD is not completely understood, it is well-documented that oxidative stress and Ca²⁺-mediated cellular damage play important roles in the progression of PD. 2-[[(1,1-Dimethylethyl)oxidoimino]-methyl]-3,5,6-trimethylpyrazine (TBN), a novel nitrone derivative of tetramethylpyrazine, has shown significant therapeutic effects in stroke models due to its multiple functions, including calcium overload blockade and free radical-scavenging. In this study, we investigated the neuroprotective and neurorescue effects of TBN on various in vitro and in vivo models of PD and explored its possible mechanisms of action. The results show that TBN exerted significant neuroprotection on 1-methyl-4-phenylpyridinium (MPP⁺)-induced damage in SH-SY5Y cells and primary dopaminergic neurons, as well as on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neuron loss in zebrafish (TBN and MPTP were added simultaneously into the fish embryo medium and the treatment period was 48 h). In the MPTP-induced mouse and 6-hydroxydopamine (6-OHDA)-induced rat PD models, TBN administrated orally twice daily for 14 d (3 d post-MPTP lesion in mice and 7 d post-6-OHDA lesion in rats) exhibited remarkable neurorescue effects to increase the number of dopaminergic neurons. In addition, TBN improved apomorphine-induced rotational behavior in the 6-OHDA-lesioned PD rats. TBN suppressed the MPP⁺-induced intracellular reactive oxygen species (ROS) in SH-SY5Y cells, increased the superoxide dismutase (SOD) activity and glutathione (GSH) concentration in the substantial nigra of MPTP-treated mice. These data indicate that TBN protects and rescues dopaminergic neurons from MPP⁺ and MPTP/6-OHDA-induced damage by reducing ROS and increasing cellular antioxidative defense capability.