Differentially expressed proteins in the E. sinensis hepatopancreas were detected after P. gregaria infection using tandem mass tag technology. Gene Ontology and Kyoto En-cyclopedia of Genes and Genomes enrichment analyses showed that the differentially expressed proteins were closely related to oxidative stress and apoptosis. Pathological sections and liver bi-ochemical indicators indicated that the liver was damaged after P. gregaria infection in the hepatopancreas of E. sinensis. Furthermore, the hepatopancreas tissue showed increased oxidative stress and apoptosis in the liver cells. This study provides a theoretical basis for understanding the pathological mechanism of P. gregaria infection in E. sinensis hepatopancreas and may guide future research directions for the prevention and treatment of P. gregaria infection.