Grouper is an important aquaculture fish with high economic value for several Asian countries. However, during growing stages, groupers are severely threatened by grouper iridovirus. In this study, we applied next-generation sequencing technology for analyzing groupers infected by two different iridoviruses of TGIV and GIV at a transciptomic level. To explore significance of differentially expressed genes, standard statistical analysis was performed. In addition, both gene ontology (GO) and cluster of orthologous groups (COG) were applied for functional annotation on genes. From the results, tilapia possessed the most number of similar sequences to grouper than all other fish model species. Besides, among the top 50 differentially expressed contigs, 19 up-regulated and 12 down-regulated genes were detected as co-expressed genes within two different iridovirus infected groupers. In contrast, there are 15 and 20 exclusively up-regulated genes and 25 and 24 exclusively down-regulated genes could be found within two different iridovirus infected groupers. These exclusively, significantly, and differentially expressed genes were considered as evidences for leading to different damages by two distinct types of iridovirus.