The Hong Kong oyster (Crassostrea hongkongesis), as the main marine aquaculture shellfish in the South China Sea, not only has high economic and ecological value, but also is an ideal model for conducting research on pathogen host interaction. Vibrio harveyi, a Gram negative luminescent marine bacterium, is widely distributed in coastal water environments, surface tissues and internal organs of marine animals, and can cause large-scale death of C. hongkongesis. However, little in formation is available on the immune response molecular mechanisms of C. hongkongesis infected with V. harveyi. Therefore, we performed transcriptome analysis of digestive diverticula of C. hongkongesis infected with V. harveyi. A total of 977689912 high quality reads and 955208562 valid reads were obtained. 6520 differentially expressed genes (DEGs) were identified, of which 3657 DEGs were up-regulated and 3255 DEGs were down-regulated during the time of infection. GO enrichment analysis showed that DEGs were mainly enriched in Cellular processes, Single-organism process, Binding, Catalytic activity, Cell, Cell part and other terms. KEGG enrichment analysis revealed that these DEGs were mainly associated with Notch signaling pathway, Necroptosis, RIG-I-like receptor signaling pathway, PPAR signaling pathway ECM-receptor interaction, Hematopoietic cell lineage, p53 signaling pathway, NF-kappa B signaling pathway, Toll-like receptor signaling pathway and other pathways are related. The results of WGCNA analysis indicated that THBS1, CA10, Svep1, Trpm2, WWOX, THAP12, PTPRT, HSPA12A, CHIA, and ADAM10 were the hub genes in the gene co-expression network. This study will provide new ideas at the transcriptome level for the immune regulatory mechanisms and adaptability of the C. hongkongesis to V. infection, as well as for achieving selective breeding for Vibrio resistance in the C. hongkongesis.