This study investigated the combined effects of seawater acidification and hypoxia on the gonadal antioxidant response of the thick shell mussel Mytilus coruscus mainly distributed along the Shengsi Island, East China Sea, where hypoxia and pH fluctuations frequently occur in summer. Mussels were exposed to three pH levels (8.1, 7.7 and 7.3) and two dissolved oxygen (DO) levels (6 and 2 mg L− 1) for 21 days following a 10-day recovery. Activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione (GSH), glutathione S-transferase (GST) and malondialdehyde (MDA) in gonad and gonad surface area (GSA) were measured at day 21 and 31. Among all the parameters, there was no significant change in SOD activity. GSA and the activity of CAT and GST were decreased under acidification and hypoxia, but GPX, GSH and MDA were increased. PCA showed that the changes were influenced by pH more than DO. Interaction between acidification and hypoxia was found significant on GPX activity and GSA. Integrated biomarker response (IBR) analysis demonstrated that acidification and hypoxia impaired mussel’s antioxidant system and increased oxidative damage. Our results clearly showed that acidification and hypoxia synergistically exert negative impact on the antioxidant system and gonad development of mussels, and the effect of acidification was more significant.