Parkinson disease (PD) is among the most common neurodegenerative disorders. The most important pathological feature of this progressive disease is aggregation of the protein alpha-synuclein (α-syn) into Lewy bodies within the neurons, leading to the loss of dopaminergic neurons in the nigrostriatal region [1]. At present, practically there is no effective cure or prevention. Therefore, development of therapeutics that target the development process of PD remains a big challenge. Mitochondria is the powerhouse of the cell. There is strong evidence linking mitochondrial dysfunction with development of PD [2]. On the other hand, mitophagy refers to a selective form of autophagy in which damaged mitochondria are degraded via the autophagy-lysosome pathway. Therefore, activating mitophagy has been considered as a logical approach in control of PD [3]. Our previous studies have shown that a stilbene compound Rhapontigenin (Rhap) could induce mitophagy to alleviate AD-like symptoms both in vitro and in vivo [4], but the effects on PD have been investigated. In this study, we revealed and identified Rhap as a potent mitophagy enhancer. Rhap alleviated 6-OHDA-induced neurotoxicity by promoting PINK1/Parkin-dependent mitophagy both in vivo and in vitro, suggesting its therapeutic potential in the PD treatment. In addition, we have further confirmed that Rhap directly bound to ACAD9 and inhibited mitochondria complex Ⅰ activity. Taken together, a novel pharmacological function of Rhap and the underlying mechanisms have been revealed, which provided an opportunity to develop Rhap as a potential therapeutic strategy against PD.