This study explored the effects of hypoxic stress on energy metabolism, oxidative stress and immune function of Onchidium reevesii. In this experiment, under hypoxic conditions [DO = (2.0 ± 0.2) mg/L], the changes of serum and hepatopancreatic biochemical indexes and the expression of hepatopancreas-related genes at 0, 4, 8, 12, and 24 h were measured. The results showed that among the energy metabolism indexes, serum blood glucose, liver glycogen, serum and hepatopancreas lactic acid levels all increased significantly with the passage of hypoxic stress. Among the antioxidant indicators, catalase (CAT) activity and reduced glutathione (GSH) content showed an upward trend and then a downward trend. All reached the maximum at 8 h, which were significantly higher than the control group. The content of malondialdehyde (MDA) showed an upward trend with the passage of hypoxic stress and was significantly higher than that of the control group. Among the immune indicators, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) showed a fluctuating upward trend, and both were significantly higher than the control group. And serum ALT and AST were higher than hepatopancreas from 8 h. The expression of glycogen phosphorylase (GP) mRNA in hepatopancreas increased significantly under hypoxic stress. The expression of glutathione peroxidase (GSH-Px) mRNA and heat shock protein 70 (Hsp70) mRNA showed an upward trend and then a downward trend, and all reached the maximum at 8 h, which was significantly different from the control group. Research showed that O. reevesii mainly carries out anaerobic metabolism in order to adapt to the hypoxic environment, and hypoxic stress affects the antioxidant capacity and immune function of the body.