The emergence of diseases such as white spot disease has become a threat to Penaeus monodon cultivation. Although there have been a few studies utilizing RNA-Seq, the cellular processes of host-virus interaction in this species remain mostly anonymous. In the present study, P. monodon was challenged with WSSV by intramuscular injection and survived for 12 days. The effect of the host gene expression by WSSV infection in the haemocytes, hepatopancreas and muscle of P. monodon was studied using Illumina HiSeq 2000. The RNA-Seq of cDNA libraries was developed from surviving WSSV-challenged shrimp as well as from normal healthy shrimp as control. A comparison of the transcriptome data of the two groups showed 2,644 host genes to be significantly up-regulated and 2,194 genes significantly down-regulated as a result of the infection with WSSV. Among the differentially expressed genes, our study discovered HMGB, TNFSF and c-Jun in P. monodon as new potential candidate genes for further investigation for the development of potential disease resistance markers. Our study also provided significant data on the differential expression of genes in the survived WSSV infected P. monodon that will help to improve understanding of host-virus interactions in this species.