To investigate the effects of cadmium (Cd) and low pH stress on antioxidant defense ability of the Chinese Mitten Crab(Eriocheir sinensis), two experimental groups with different pH values (7.8, 6.5), and three experimental groups with different Cd²⁺ concentrations (0 mg/L, 1.45 mg/L and 2.9 mg/L), were set and exposed for 7 d, 14 d, and 21 d, respectively. The effects of cadmium and low pH stress on total hemocyte counts (THC), serum superoxide dismutase (SOD) activity, catalase (CAT) activity, total antioxidant capacity (T-AOC), malondialdehyde (MDA) content and four immune related genes (glutathione peroxidase (GPx), glutathione S-transferase (GST), heat shock protein 70 (HSP70), lysozyme (LZM) mRNA in hepatopancreas of Eriocheir sinensis were studied. The results showed that THC decreased significantly with the increase of Cd concentration, and THC at pH 6.5 was lower than that at pH 7.8. When the pH value was 7.8, with the increase of cadmium concentration, the activities of SOD and T-AOC in serum increased first and then decreased, while the activities of CAT (except the 7th day) and the content of MDA increased gradually. The activities of SOD, CAT, and T-AOC were significantly lower than those of pH 7.8 (P<0.05). During the whole experiment, the content of MDA at 2.9 mg/L and pH 6.5 was significantly higher than that at pH 7.8 (P<0.05). When pH value was 7.8, the mRNA expression levels of GPx, GST, HSP70 and LZM increased gradually with the increase of cadmium concentration. When cadmium concentration was 2.9 mg/L for 21 days, the gene expression levels reached the highest. On the 14th and 21st day, the expression of GPx and GST mRNA at 2.9 mg/L and pH 6.5 of cadmium was significantly decreased, which was significantly lower than that at pH 7.8 of the same concentration (P<0.05), while the expression of HSP70 and LZM mRNA was significantly decreased only on the 21st day, which was also significantly lower than that at pH 7.8 of the same concentration (P<0.05). In general, the activity and content of antioxidant enzymes and the mRNA expression of related genes were up-regulated or down regulated in response to oxidative stress. The effect of low pH and cadmium on the antioxidant defense of Eriocheir sinensis was much greater than that of single factor, especially high concentration of cadmium (2.9 mg/L). The results provide a theoretical basis for the future study of the impact of water acidification and heavy metal pollution on crustaceans.