Blood cockles, Anadara granosa, live in coastal mudflats under threaten of low-dose chronic heavy metal exposure. The toxic effects of low dose chronic copper (7.1, 14.2, and 28.4 μg/L), lead (43, 86, and 172 μg/L), and cadmium (55, 110, and 220 μg/L) exposure on the antioxidant enzyme activities in gill, gonad and digestive gland of A. granosa were investigated in this study. The activities of superoxide dismutases (SOD), catalase (CAT) and glutathione peroxidase (GPx) fluctuated with increased copper, lead, and cadmium exposure time. The heavy metal exposure concentration and duration (7, 14, 21, and 28 days) showed significant effects on the antioxidant enzyme activities in tested tissues. Moreover, the activities of tested antioxidant enzymes not only varied among different tissues, but also were dependent on metal species, suggesting the reactive oxygen species (ROS) may be produced through different mechanisms for different metals in various tissues. Our results indicate that the application of antioxidant enzyme activities as endpoints in toxicology bioassays for chronic sub-lethal metals must be done with caution due to their complicated produce mechanisms.