In this study, a novel hypoglycemic peptide Gly-Pro-Ala-Gly-Ala-Pro (GPAGAP) was screened from skin collagen hydrolysates of Andrias davidianus by network pharmacology and bioinformatics, and its hypoglycemic mechanism was predicted. Meanwhile, the improvement of insulin resistance (IR) in HepG2 cells were detected. Through network pharmacology screening, GPAGAP had good drug-like properties, and 105 targets of GPAGAP overlap with diabetes mellitus type 2 (T2DM) targets. These targets were mainly enriched in the PI3K-Akt signaling pathway, TNF signaling pathway, IR and other signaling pathways related to T2DM. The results of IR-HepG2 cell model experiments showed that GPAGAP could reduce IR of HepG2 cells induced by high-glucose and high-insulin, and improve glucose consumption of IR-HepG2 cells. GPAGAP could increase the glycogen content, hexokinase (HK) and pyruvate kinase (PK) activities of IR-HepG2 cells, inhibit the accumulation of triglyceride (TG) and total cholesterol (TC) in IR-HepG2 cells, and enhance the activity of superoxide dismutase (SOD) in IR-HepG2 cells, reduce the content of malondialdehyde (MDA) and reactive oxygen species (ROS) in IR-HepG2 cells. The above results suggested that GPAGAP could through multi-target and multi-pathway to improve the glucose metabolism, lipid metabolism and oxidative stress response of IR-HepG2 cells. It has the potential effect of improving insulin resistance in T2DM.