The frequent occurrence of cyanobacterial blooms (CYBs) caused by toxic Microcystis aeruginosa poses a great threat to aquatic organisms. Although freshwater benthic bivalves have proven to be capable of uptake high levels of microcystins (MCs) due to their filter-feeding habits, there is a paucity of information concerning their systemic resistance mechanisms to MCs. In this study, the resistance mechanisms in Corbicula fluminea (O. F. Müller, 1774) in response to the exposure of toxic M. aeruginosa were explored through transcriptional analysis combined with histopathological and biochemical phenotypic analysis. Toxic M. aeruginosa exposure caused dose-dependent histological damage in the hepatopancreas. The conjugation reaction catalyzed by glutathione S-transferases was vulnerable to being activated by high concentrations of M. aeruginosa (10 ×105 cells mL−1). Additionally, reactive oxygen species scavenging processes mediated by superoxide dismutase and catalase were active in the initial stage of toxic M. aeruginosa exposure. The results of the integrated biomarker response index suggested that the biotransformation and antioxidant defense system in C. fluminea could be continuously activated after acute exposure to the high concentration of toxic M. aeruginosa. The eggNOG and GO analysis of the differentially expressed genes (DEGs) indicated that DEGs were significantly enriched in transporter activity, oxidant detoxification and response to oxidative stress categories, which were consistent with the alterations of biochemical indices. Besides, DEGs were significantly annotated in a few KEGG pathways involved in biotransformation (oxidation, cooxidation and conjugation) and immunoreaction (lysosome and phagosome responses), which could be responsible for the tolerance of C. fluminea to toxic M. aeruginosa. These findings improve our understanding of potential resistance mechanisms of freshwater bivalves to MCs.