The Zhikong Scallop, Chlamys farreri, is one of the most important bivalve mollusks cultured in northern China. However, mass mortality of the cultured C. farreri has posed a serious threat to the maricultural industry in recent years. Acute Viral Necrobiotic Virus (AVNV) is believed as an important etiological agent causing the scallop mass mortalities. To understand the mechanism behind the AVNV associated scallop disease and mortality, we assessed the physiological and immune responses of C. farreri to the virus infection using oxygen consumption rate, ammonium-nitrogen excretion rate, hemocyte copper, zinc superoxide dismutase gene expression, and plasma superoxide dismutase activity and alkaline phosphatase activity as indicators. Scallops challenged by AVNV at 25 °C developed typical disease signs 2 days after virus injection. Before the disease manifested, scallop oxygen consumption and NH 4 + –N excretion rates rose and then fell back. Real-time PCR revealed that the hemocyte cytosol Cu, Zn SOD gene expression was upregulated followed by recovery. The plasma SOD activity, however, augmented consistently following virus injection. Moreover, plasma AKP activity first lowered and then elevated gradually to the highest level at 24 h post virus injection. Scallops challenged by AVNV at 17 °C neither developed notable disease nor showed obvious responses that could be associated with the virus infection. While the results suggested a correlation between the elevated seawater temperature and the AVNV infection associated C. farreri mortalities, they also indicated that the viral infection provoked multiple physiological and immune responses in the host scallops.