Recently, the nanozyme Pd@Pt has garnered attention due to its notable specific surface area and superior enzyme-like catalytic activity, leading to extensive examination and application in previous studies. However, the comprehensive impact of Pd@Pt nanozyme on treating metabolic disorders, such as diabetes and its associated conditions, remains largely unexplored. This research aimed to clarify how Pd@Pt influences metabolic balance at both the transcriptome and microbiome levels and to explore the interactions between microbiota and genes. We conducted an examination of mice subjected to a high-fat diet (HFD) following treatment with Pd@Pt. Transcriptome analysis was performed to identify differentially expressed genes (DEGs), and microbiome analysis was conducted to identify significant bacterial correlations associated with Pd@Pt exposure. The results indicated enhancements in glucose metabolism dysfunctions in the treated mice. Transcriptome analysis revealed that DEGs after Pd@Pt administration were enriched in the PI3K-Akt, NF-κB, and MAPK signaling pathways in the liver. Microbiome analysis identified four significant bacteria that exhibited a strong negative correlation with Pd@Pt exposure, while ten bacteria showed a positive correlation. Furthermore, a correlation network established among the gut microbiota, metabolites, and DEGs demonstrated a robust association. This research enhances our understanding of the mechanisms by which Pd@Pt affects the regulation of metabolic diseases in HFD-exposed environments and proposes a novel strategy for utilizing nanozymes in human health management.