Parkinson's disease (PD) is a progressive neurodegenerative condition. The pathogenesis of PD is still unknown, and drugs available for PD treatment either have side effects or suboptimal efficacy. Flavonoids are potent antioxidants having little toxicity with extended use, suggesting they might hold promising therapeutic potential against PD. Vanillin (Van), a phenolic compound that has exhibited neuroprotective properties in various neurological disorders, including PD. However, the neuroprotective role of Van in PD and its underlying mechanisms are scarce and therefore need more exploration. Here, we evaluated the neuroprotective potential of Van and its associated mechanisms against MPP + /MPTP-induced neuronal loss in differentiated human neuroblastoma (SH-SY5Y) cells and PD mice model. In the present study, Van treatment significantly enhances the cell viability, alleviates oxidative stress, mitochondrial membrane potential and apoptosis in MPP + -intoxicated SH-SY5Y cells. Moreover, Van significantly ameliorated the MPP + -induced dysregulations in protein expression of tyrosine hydroxylase (TH) and mRNA expressions of GSK-3β, PARP1, p53, Bcl-2, Bax and Caspase-3 genes in SH-SY5Y cells. Similar to our in vitro results, Van significantly alleviated MPTP-induced neurobehavioral dysregulations, oxidative stress, aberrant TH protein expressions and immunoreactivity in SNpc of mice brains. Treatment of Van also prevented MPTP-mediated loss of TH-positive dopaminergic neurons intrinsic to SNpc and TH-fibers projecting to the striatum of mice. Thus, Van exhibited promising 2 neuroprotective properties in the current study against MPP + /MPTP-intoxicated SH-SY5Y cells and mice, indicating its potential therapeutic properties against PD pathology.