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<i>Macrobrachium nipponense</i> is a significant cultivated species in China. However, decapod iridescent virus 1 (DIV1), as a newly discovered crustacean-lethal virus, has resulted in significant financial losses for the <i>M. nipponense</i> industry. In order to examine the immunological response of <i>M. nipponense</i> to DIV1, we conducted transcriptome analysis of the hepatopancreas from <i>M. nipponense</i> infected with DIV1 using RNA-seq. RNA sequencing analysis identified a combined total of 41,712 assembled unigenes, and 7014 genes that showed differential expression were identified in the group infected with DIV1, compared to the control group. Among these DEGs, 3952 were found to be up-regulated, while 3062 were down-regulated; many well-characterized DEGs were involved in innate immune defense, particularly involving the C-type lectin receptor signaling pathway, complement and coagulation cascades, phagosome, lysosome and PPAR signaling pathway. Moreover, the expression levels of well-known immune-related genes (<i>dorsal</i>, <i>wnt6</i>, <i>lectin</i>, <i>caspase</i>, <i>integrin</i>, <i>hsp70</i>) in the hepatopancreas and hemolymph were investigated by Quantitative real-time PCR (qRT-PCR), and the findings demonstrated a significant increase in gene expression in the hepatopancreas and hemolymph at various time points after infection. The results acquired in this study offered further comprehensive understanding of the immunological response of <i>M. nipponense</i> to DIV1 infection.