Abstract: Enzymatic hydrolysates of purple sweet potato polyphenol-protein complexes (PPPCs) exhibited potential hypoglycemic activity. In this study, PPPCs were synergistically hydrolyzed using papain and alkaline protease, followed by fractionation through 3 kDa and 10 kDa ultrafiltration membranes to obtain three peptide fractions (fraction 1: <3 kDa, fraction 2: 3~10 kDa, and fraction 3: >10 kDa). The hypoglycemic effects of these fractions were evaluated in a diabetic mice model induced by a high-fat diet and streptozotocin (STZ) injection. The most active peptide fraction was further purified by gel chromatography, and its glucose uptake-enhancing activity was assessed using an insulin-resistant HepG2 cell model. Results showed that the group of high-dose fraction 1 (D+H1) in the treatment groups exhibited the most potent hypoglycemic effect. Compared with the modeling group without treatment (D+HF), mice in this group demonstrated significantly reduced fasting blood glucose levels (P<0.05), markedly improved glucose tolerance (P<0.05), and significant amelioration of diabetes-induced weight loss and damage to the liver, kidneys, and heart (P<0.05). Levels of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) in serum were significantly reduced (P<0.05), while high-density lipoprotein cholesterol (HDL-C) levels were significantly elevated (P<0.05). Notably, its subfraction 1 (Peak 1) significantly increased glucose consumption in insulin-resistant HepG2 cells by 16.20% at a concentration of 0.1 mg/mL (P<0.05). This study confirmed that enzymatic hydrolysates of PPPCs possessed potent hypoglycemic properties. Among them, the <3 kDa peptide fraction had the best hypoglycemic effect and exhibited a certain degree of dose dependency, and its hypoglycemic activity primarily originated from its subfraction 1. These findings provide a theoretical foundation for developing purple sweet potato-derived bioactive peptides as nutritional interventions for diabetes. Additionally, this study highlights the potential for high-value utilization of agricultural byproducts in functional food applications.