Oriental river prawn, Macrobrachium nipponense, is a commercially important species found in brackish and fresh waters throughout China. Chronic hypoxia is a major physiological challenge for prawns in culture, and the hepatopancreas, muscle and gill tissues play important roles in adaptive processes. However, the effects of dissolved oxygen availability on gene expression and physiological functions of those tissues of prawns are unknown. In this study, we performed comparative transcriptome profiling of Macrobrachium nipponense in response to hypoxia, and identified a relatively large number of genes that displayed distinct differences in expression in hepatopancreas, muscle and gill tissues. Overall, our transcriptome map may provide significant insights into the underlying molecular mechanisms that govern the responses of M. nipponense to hypoxia stress. The hypoxia induced and reduced genes identified may prove to be potential candidates for global geneti c engineering of salt tolerance in M. nipponense. The pathways, the gene expression patterns and histological variations in gills and hepatopancreas tissues provide insight into understanding the molecular mechanisms of hypoxia in crustaceans.