Fluoxetine (FLX), a selective serotonin reuptake inhibitor, is widespread in aquatic environments. Despite its reported effects on behavior and reproduction in aquatic species, little is known about the effects of FLX on cellular detoxification and defense system in bivalves. Here, the adult Asian clam (Corbicula fluminea) was exposed to 0.5, 5, and 50μgL−1 FLX for 30d. Siphoning behavior was inhibited by treatment with 50μgL−1 FLX. Additionally, superoxide dismutase (SOD) activity in the gills and digestive glands significantly decreased (p<0.05) with 5 and 50μgL−1 FLX treatments, whereas catalase (CAT) activity and malondialdehyde (MDA) content markedly increased (p<0.05). Moreover, transcription of thioredoxin reductase (TR), glutathione peroxidase (GPx) and Glutathione S-transferase pi class (GSTpi) was significantly upregulated (p<0.05), whereas glutathione reductase (GR) was markedly downregulated (p<0.05). These findings suggest that FLX affects behavior and induces oxidative stress in C. fluminea. The downregulation of ATP-binding cassette (ABC) transportor genes (ABCB1, ABCC1 and ABCG2) transporter genes indicated that FLX might suppress the multixenobiotic resistance (MXR) system in C. fluminea. Our results provide new insights into the adverse effects of FLX on the cellular detoxification and MXR system of C. fluminea.