As an economically important bivalve, the Mytilus coruscus is cultured widely in the eastern coast of China. In recent years, this bivalve has been seriously affected by the pathogenic infections. To elucidate the host defense mechanisms of M. coruscus against pathogenic challenge, the hemocyte transcriptomes of M. coruscus before and after Vibrio alginnolyficus infection were analyzed using the deep-sequencing platform Illumina/HiSeq-2500, meanwhile the differentially expressed genes (DEGs) were investigated. In total, 130,031,083 clean reads were obtained and then assembled into 63,942 unigenes with an average length of 810 bp and an N50 of 1056 bp. Unigenes were annotated by comparing against nr, Swiss-Prot, KEGG, COG, KOG, GO, and Pfam databases, and 27,345 unigenes (42.77%) were annotated in at least one database. After bacterial challenge, 1270 and 265 genes were identified as remarkably up- or down-regulated, respectively, amongst 1154 were associated with 122 pathways, including classical immune-related pathways, such as ‘Toll-like receptor signaling’, ‘the complement cascades’, ‘MAPK signaling pathway’, ‘Apoptosis’ and ‘Wnt signaling pathway’. Besides, nine genes which were differently-expressed immuno-related were confirmed by using quantitative real-time PCR. These findings would provide new insights on the M. coruscus innate immunity, based on which, some novel strategies for management of diseases and long-term sustainability of M. coruscus culture could be developed.