Parkinson's disease (PD) is a neurological disorder characterized by motor and gastrointestinal dysfunctions. Resveratrol is a potent antioxidant and anti-inflammatory phytoalexin known for its health-promoting benefits. However, little is known about its potential in treating PD by modulating the microbial gut-brain axis, and its clinical application has been limited due to poor water solubility, rapid metabolism, and limited systemic bioavailability. Our study aimed to evaluate the therapeutic potential of RHSD, a resveratrol-cyclodextrin inclusion complex, in treating PD through the gut-brain axis in human SNCA-transgenic (A53T) mice PD models. Building on our previous study, we prepared RHSD and compared its efficacy with uncoated resveratrol for PD treatment. The study results demonstrated that RHSD exhibited several advantages in improving motor function, alleviating cognitive impairment, restoring intestinal barrier function, and inhibiting neuropathy. Subsequently, a series of analyses, including fecal microbiota metagenomic sequencing, non-target metabolic assays, host transcriptome sequencing, and integrative analysis were performed to reveal the potential therapeutic pathways of RHSD in A53T mice. The metagenomic sequencing results indicated a significant increase in the levels of Lactobacillus murinus, Lactobacillus reuteri, Enterorhabduscaecimuris, Lactobacillus taiwanensis, and Lactobacillus animals following RHSD administration. Furthermore, metabolomics profiling showed that the levels of gut microbiome metabolites were reversed after RHSD treatment, and differential metabolites were significantly correlated with motor function and intestinal function in PD mice. The integrated analysis of microbial metabolites and host transcriptomics suggested that abnormal amino acid metabolism, mitochondrial dysfunction, oxidative stress, and neuroinflammation in the PD model were associated with the diffusion of abnormal metabolites. This study illustrates the profound impact of RHSD administration on rectifying gut microbiota dysbiosis and improving the A53T mouse model. Notably, we observed significant alterations in the proliferation and metabolism of multiple probiotic strains of Lactobacillus. Furthermore, our research supports the hypothesis that microbiota-related metabolites may regulate the transcription of host genes, including dopamine receptors and calcium stabilization. Consequently, our findings underscore the potential of RHSD as a promising therapeutic candidate for the treatment of PD through the modulation of several signaling pathways within the microbiota–gut–brain axis.