Background: Type 2 diabetes mellitus (T2DM) frequently coexists with metabolic dysfunction-associated fatty liver disease (MAFLD), contributing to glucose and lipid metabolism disorders and hepatic injury. Shenzhu Tiaopi granule (STG) has shown beneficial effects on metabolism, but the molecular basis remains unclear. Objective: This study aimed to identify candidate proteins associated with the metabolic effects of STG. Methods: A T2DM combined with MAFLD rat model was established by feeding Goto-Kakizaki (GK) rats a high-fat diet. The metabolic and hepatic effects of STG were evaluated by biochemical and histopathological analyses. Hepatic proteins were analysed using data-independent acquisition (DIA)-based quantitative proteomics followed by integrated bioinformatics analysis. Candidate proteins were evaluated using public datasets and experimental validation. Molecular docking and molecular dynamics (MD) simulations were used to investigate interactions between AMY1A and certain STG components, and selected interactions were validated by surface plasmon resonance (SPR). Results: STG improved hyperglycaemia, insulin resistance, abnormal lipid metabolism, and pathological changes in the liver. Proteomic analysis revealed that the proteins regulated by STG were related mainly to glucose, lipid, and energy metabolism. The integrated analysis identified Amy1 as a potential key protein. AMY1A was subsequently evaluated using public datasets and further investigated experimentally. AMY1A expression decreased in model rats but increased after STG treatment. Molecular docking and MD simulations suggested potential interactions between AMY1A and five STG components, namely, stigmasterol, β-sitosterol, quercetin, luteolin, and baicalin. SPR confirmed the direct binding of stigmasterol and β-sitosterol to AMY1A. Conclusion: STG alleviated metabolic and hepatic abnormalities in T2DM rats with MAFLD. AMY1A was identified as a candidate protein associated with STG intervention, providing a basis for further investigation of its role in the metabolic effects of STG.