Dibenzocyclooctadiene lignans represent a unique group of natural chemical structures. They are protective against neuronal cell death and cognitive impairment in neurological disorders such as stroke and neurodegenerative diseases. Among the studies on the dibenzocyclooctadiene lignans from the fruit of S. chinensis, there is a lack of data about the neuroprotective action of schisantherin A(StA) and its potential for use as a therapeutic agent against Parkinson’s disease (PD). In an attempt to identify effective neuroprotectants from dibenzocyclooctadiene lignans for the prevention/treatment of PD, two commonly used dopaminergic (DA) neurotoxins, 1-methyl-4-phenylpyridinium ion (MPP+ ) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), were applied to induce neuronal damage in vitro, and in zebrafish and mice in vivo. This study involves a comprehensive structure activity relationship analysis and an in-depth mechanistic assessment of the protective effect of StA, in multiple experimental models of PD. The proteomics and pharmacokinetics of StA, and the bioavailability after different formulation of StA administrated were investigated. Our results have demonstrated that treatment with StA significantly inhibited MPP+ -induced cytotoxicity, prevented caspase-3 activation and increased Bcl-2 expression in SH-SY5Y cells. Moreover, StA conferred significant protection against MPTP-induced damage in TH-positive dopaminergic neurons in PD zebrafish and mice model. The present study provides direct evidence StA exhibited neuroprotection against MPP+ through the regulation of two distinct pathways including increasing CREB-mediated Bcl-2 expression and activating PI3K/Akt survival signaling. Our proteomic profiles provide new insights into possible involvement of diverse functional proteins, which play an important role in controlling myopathy, fatty acid synthases, oxidative stress and calcium homeostasis in the neuroprotective effects of StA in 6-OHDA-induced PC12 cells. StA demonstrated poor oral bioavailability, while nanoemulsion formulation could significantly increase its oral bioavailability. Our study also supported the notion that StA could pass through the blood-brain barrier (BBB). This is the first study to demonstrate the neuroprotective action of StA on MPTP/MPP+ -induced PD models, and provide insight into its mechanism of action in MPP+ /6-OHDA-induced neurotoxicity. In view of that, StA exhibits neuroprotection against MPP+ through the regulation of two distinct pathways including increasing CREB-mediated Bcl-2 expression and activating PI3K/Akt survival signaling and good oral bioavailability of its nanoemulsion formulation, StA is a promising therapeutic agent for the prevention of PD by oral delivery.