Harmful algal blooms (HABs) and thermal stress as climate changes become more common in global water ecosystem, especially under eutrophic habitats. Here our study examined the combined impacts of bloom forming cyanobacteria Microcystis aeruginosa and thermal stress on the antioxidant responses of the ecologically important species triangle sail mussel Hyriopsis cumingii. The differential responses of a series of enzymes, e.g. superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione-S-transferase (GST), as well as signal metabolites including reactive oxygen species (ROS), malondialdehyde (MDA) and glutathione (GSH) involved in antioxidant defense mechanisms were analyzed during 14 d exposure to toxic cyanobacterium M. aeruginosa and 7 d depuration period. The activities of SOD and GPx as well as the content of ROS and MDA in H. cumingii increased, while CAT activity reduced due to M. aeruginosa exposure. Thermal stress resulted in decrease of CAT, the accumulation of GSH and the enhance of GST and SOD. Meanwhile, the interactive effects among M. aeruginosa, thermal stress and time were also observed on most parameters except for GST activity. The total amount of microcystins (MC) in sail mussels increased with concentrations of exposed M. aeruginosa, independently of the presence or absence of thermal stress. Although around 50% of MC in mussels dropped in the depuration period, most parameters showed alterations because of cyanobacteria exposure and thermal stress. Overall, these findings suggested that toxic cyanobacteria or thermal stress induces oxidative stress and severely affects the enzymes activities and intermediates level associated with antioxidant defense mechanisms in sail mussels respectively. More importantly, the toxic impacts on sail mussels could be intensified by their combination.