Parkinson’s disease (PD) is a common neurodegenerative disease characterized by a disorder of the dopaminergic system in the midbrain, causing classical PD motor symptoms. The therapeutic effect of cannabidiol (CBD) on PD has been a research frontier in recent years. However, the pathogenesis of PD and the therapeutic mechanism of cannabinoid remain unclear. To further study the causes of PD and the effect of CBD on PD, we exposed the PD transgenic mouse model to CBD and then estimated the motorial and postural coordination through a modified swim test. Afterwards, the mechanism was investigated via the histopathology of substantia nigra and the gut-brain metabolic analysis in the approach of UHPLC-TOF-MS. The results showed that CBD significantly improved motor deficits of PD model and protected the substantia nigra area. The metabolic function of fatty acid biosynthesis, arginine biosynthesis/metabolism, butanoate (ketone body) metabolism, β-alanine metabolism, and pantothenate/CoA biosynthesis was highlighted in the pathological and therapeutic process along the gut-brain axis. In conclusion, CBD could attenuate PD via the neuroprotective effect on the midbrain. The attenuation of the central nervous system in turn improved motor performance of PD, which might be partially induced by the metabolic interaction between the gut-brain. In view of gut-brain metabolomics, the mechanism of PD pathogenesis and the effect of CBD on PD are highly related to the biosynthesis and metabolism of energy and essential substance. CLICK TO REVIEW