Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting movement, with no treatments currently available to halt or slow its progression. Therefore, the development of new anti-PD drugs is urgently needed. As a kind of medicine and food homologous plant, Cistanches Herba has a promising future for the treatment of PD. In this study, a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model was used to detect Cistanches Herba’s anti-PD effects via histopathology and molecular biology. Simultaneously, the effect of Cistanches Herba on the “gut microbiota-barrier axis” was assessed through gut microbiota and intestinal barrier function in mice. Finally, transcriptomics analysis was conducted to further verify the results. As a result, 37 differential metabolites and 16 microbial genera were screened and tentatively identified. Thirty-two metabolites and sixteen microbial genera were simultaneously altered with opposing trends in variation after MPTP and Cistanches Herba treatments. We built a framework for predicting targets and hostmicrobe interaction mechanisms, as well as identifying alternative treatment for PD, which should be validated further for clinical application. In conclusion, Cistanches Herba exerts a protective effect against the development of PD by manipulating the structural feature of intestinal flora to influence the host metabolites.