Diabetes has become a significant disease threatening human health and social development. Food intervention is considered an essential strategy to prevent early diabetes development sustainably. The natural product, 1,2,3,4,6-penta-O-galloyl-β-D-glucose (PGG), commonly found in fruits and diets, has many potential antihypoglycemic, antibacterial, and antitumor activities. We found that PGG can promote glucose uptake in whole-organism zebrafish screening, which help in downregulating the glucose levels. We investigated the metabolome and transcriptome changes in zebrafish exposed to high glucose and PGG intervention. The differential genes and metabolites were screened out based on the comparisons of blank, hyperglycemic, and the PGG-exposed groups of zebrafish larvae. Combined with RT-qPCR validation, we found that PGG mainly restored four genes (fthl27, LOC110438965, plat, and aacs) and six metabolites abnormally invoked by high glucose. These validated genes are related with the key metabolites sphingosine and (R)-3-hydroxybutanoate involving the pathways of apelin, apoptosis, necroptosis, and butanoate metabolism. Our findings provided a new mechanistic basis for understanding the hypoglycaemic function of the commonly present dietary molecule (PGG) and offered a new perspective for the rational utilization of PGG to regulate metabolic disorders.