Acute hepatopancreas necrosis disease (AHPND) has caused massive deaths of shrimp and has led to huge economic losses in aquaculture. Vibrio parahaemolyticus (VPAHPND) carrying a plasmid encoding binary toxins homologous to the photorhabdus insect-related (Pir) toxins is one of the main pathogens causing this disease. Previous studies have reported many immune-related genes of shrimp in response to this pathogenic bacteria. However, few studies have so far focused on the metabolic changes in Litopenaeus vannamei upon VPAHPND infection. In the present study, comparative transcriptomic analysis was performed on the hepatopancreas of shrimp at different times during VPAHPND infection. Functional analyses on the differentially expressed genes (DEGs) during infection showed that pathways related to glucose, energy and amino acid metabolism, as well as nucleic acid synthesis, were obviously changed in the hepatopancreas after VPAHPND infection. Additionally, three signaling pathways, which could regulate metabolic processes, including HIF-1 signaling pathway, PI3K-Akt signaling pathway and NF-KappaB signaling pathway, also changed significantly. Collectively, these data reveal a close relationship between host metabolism processes and Vibrio infection. The information will enrich our understanding of the interaction mechanism between the shrimp and Vibrio.