: As a typical chronic metabolic disease, type 2 diabetes mellitus causes a heavy health-care burden to society. In this study, we applied the metabolomics strategy to explore the potential molecular mechanism of the Huangqiliuyi decoction (HQLYD) for type-2 diabetes (T2D). Ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) combined with pattern recognition methods was utilized to select specific metabolites closely associated with HQLYD. Biomarker pathway analysis and biological network were utilized to uncover the therapeutic effect and action mechanism related to HQLYD. A total of twenty-five biomarkers were identified in the animal model, in which sixteen biomarkers are associated with HQLYD treatment for T2D. They attenuated the abnormalities of metabolic pathways such as phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, and the citrate cycle. HQLYD also significantly elevated the serum FINS and SOD, GSP-x level in the liver and kidney, and reduced the serum TC, TG, HDL, LDL, urea, Scr, AST, ALT, FBG, IRS, MDA, and CAT level. We found that the therapeutic mechanism of HQLYD against T2D affected amino acid metabolism, glucose metabolism and lipid metabolism. Metabolomics revealed that the Huangqiliuyi decoction attenuates abnormal metabolism as a novel therapeutic opportunity for type 2 diabetes.