The Pacific white shrimp (Penaeus vannamei) is an economic breeding species with the largest annual production of penaeid shrimp worldwide. Besides the V. parahaemolyticus strains causing acute hepatopancreatic necrosis disease (AHPND), the non-AHPND V. parahaemolyticus strains also cause severe disease leading to significant economic losses in the shrimp. A non-AHPND V. parahaemolyticus strain, named TJA114, isolated from P. vannamei with vibriosis exhibited strong pathogenicity toward the shrimp. To better understand the pathogenesis of P. vannamei in the early stage of non-AHPND V. parahaemolyticus infection, we performed mRNA sequencing for the hepatopancreas between the control and the V. parahaemolyticus-challenged groups at six hours post-infection. We identified 916 differentially expressed genes: 550 up-regulation and 366 down-regulation in the challenged shrimp. GO terms related to immunity and metabolism were annotated, including biological adhesion, response to stimulus, metabolic process, binding, and cellular process. KEGG pathways related to fatty acid elongation, C-type lectin receptor signaling and complement and coagulation cascades were significantly influenced by the V. parahaemolyticus infection. This study provides insights into the mechanisms by which P. vannamei responds to early infection with the non-AHPND V. parahaemolyticus.