Ruditapes philippinarum is one of the most commercially important bivalve shellfish. However, the clam aquaculture industry has faced a great challenge due to Vibrio parahaemolyticus in recent years. In this study, we performed RNA-seq to profile the transcriptome of hepatopancreas tissue in the R. philippinarum with resistant individuals (survival group, VpS) and susceptible individuals (moribund group, VpM) after V. parahaemolyticus infection. A total of 1082 and 1876 differentially expressed genes were identified in the VpS group and VpM group after infection, respectively. The KEGG analysis reveal that immune related functional genes were significantly enriched in AMPK (5’-AMP-activated protein kinase), mTOR (mammalian target of rapamycin) signaling pathway, Autophagy and Lysosome, and phagosome in the hepatopancreas of Manila clams under V. parahaemolyticus challenge. For the RNA-seq validation, we verified 14 immune related DEGs by real-time quantitative PCR (qPCR). In addition, histological observation of hepatopancreas from Manila clam after V. parahemolyticus challenge was conducted and inflammatory response in tissues were appeared from the pathological morphology. The results obtained in this work provide valuable insights into the immune function of R. philippinarum under V. parahaemolyticus challenge.