In order to explore the composite pollution toxicity mechanism of microplastics and perfluorooctane sulfonate (PFOS) in Perna viridis, the effects of PFOS (10, 100, 1000 μg/L) and microplastics (0.2 μm, 4.55×108 numbers/L) were studied under single- or co-exposure on the filtration rate, reactive oxygen level (ROS), malondialdehyde (MDA) content, superoxide dismutase (SOD) activity, catalase (CAT) activity, glutathione S-transferase (GST) activity and gluathione reductase (GR) activity. The results showed that the filtration rate of mussels after exposure to microplastics and PFOS did not change significantly compared to the solvent control. In gills, visceral mass and gonads of mussels, the stress of microplastics and PFOS could cause significant changes in enzyme response. After co-exposure of microplastics and 1000 μg/L PFOS, compared with single-PFOS exposure groups, ROS level significantly increased in gills and gonads, whereas decreased in visceral mass; MDA content increased in gills and visceral mass, whereas decreased in gonads; GST and GR activity was significantly reduced in gills, whereas increased in gonads. The results indicated that microplastics could change the oxidative stress response of mussels to PFOS.