Microcystin-LR (MC-LR), a hepatotoxin, is a potent threat to fish. In this study, we characterized the differential expression of grass carp liver after injected with 25 (T1), 75 (T2) and 100 (T3) μg MC-LR/kg body weight for 96 h. A total of 457 common differentially expressed genes (DEGs) were identified using RNA-Seq between three treated groups (T1, T2 and T3) and control group (C). Of these DEGs, 61, 203 and 129 immune-related genes were regulated in T1 vs. C, T2 vs. C and T3 vs. C, respectively. The significant altered transcript levels, including MHC IIα, IgLC, SOCS3, indicated a disruption of the immune system. Based on GO and KEGG enrichment analysis, among which affected signaling pathways, 24 pathways were immune-related, specifically, “complement and coagulation cascades”, which was highly enriched in three treated groups. The key genes of complement and coagulation cascades, such as Factor III and Factor VIII might be related with the mechanisms of immune toxicology of MC-LR and they could be used as sensitive biomarkers for MC-LR risk assessment. Furthermore, the damages in liver including vacuolar, hemorrhage and loss of nuclei caused by MC-LR have been verified in this study. The present study shows a systematic overview of the transcriptome analysis in grass carp, and the identified important immune-related genes and signaling pathways that will provide useful insights for further analysis of the mechanisms of MC-LR.