Abstract Oxidative stress (OS) plays a pivotal role in the pathogenesis of Parkinson's disease (PD). 6-Hydroxydopamine (6-OHDA) is a neurotoxin used to induce oxidative cell death of dopaminergic neurons in experimental models of PD. Curcumin I, or diferuloylmethane is a pure compound isolated from Curcuma longa Linn. that has been reported to have neuroprotective properties. The precise mechanism, however, remains unclear. This study aims to elucidate the mechanisms by which curcumin I exerts its effects, using 6-OHDA-induced neurotoxicity in the human dopaminergic cell line SH-SY5Y. In our experiments, pretreatment with curcumin I improved cell viability, and significantly reduced reactive oxygen species (ROS). Further investigations revealed a reduction of p53 phosphorylation and decrease of the Bax/Bcl-2 ratio, as measured by mRNA expression and protein level. Taken together, these findings indicate that curcumin I protects dopaminergic neurons from 6-OHDA-induced toxicity via the reduction of ROS production, and subsequent attenuation of p53 phosphorylation and reduction of the Bax/Bcl-2 ratio.