Ocean acidification (OA) has been found to increase the release of free Cu 2+ in seawater. However, only a handful of studies have investigated the influence of OA on Cu accumulation and cellular toxicity in bivalve species. In this study, Pacific oysters, Crassostrea gigas, were exposed to 25 μg/L Cu 2+ at three pH levels (8.1, 7.8 and 7.6) for 14 and 28 days. Physiological and histopathological parameters [(clearance rate (CR), respiration rate (RR), histopathological damage and condition index (CI)), oxidative stress and neurotoxicity biomarkers [superoxide dismutase (SOD) and glutathione transferase (GST) activities, lipid peroxidation (LPO) and acetylcholinesterase (AChE) activity], combined with glycolytic enzyme activities [pyruvate kinase (PK) and hexokinase (HK)] were investigated in C. gigas. The bioconcentration of Cu was increased in soft tissues of Cuexposed oysters under OA. Our results suggest that both OA and Cu could lead to physiological disturbance, oxidative stress, cellular damage, disturbance in energy metabolism and neurotoxicity in oysters. The inhibited CR, increased glycolytic enzymes activities and decreased CI suggested that the energy metabolism strategy adopted by oysters was not sustainable in the long term. Furthermore, integrated biomarker response (IBR) results found that OA and Cu exposure lead to severe stress to oysters, and co-exposure was the most stressful condition. Results from this study highlight the need to include OA in future environmental assessments of pollutants and hazardous materials to better elucidate the risks of those environmental perturbations.