Ruditapes philippinarum is one of the most important shellfish species cultured on the beach in China. In recent years, global climate change and coastal seawater eutrophication have expanded the hypoxic area of the tidal flat ecosystem. The severity and duration of hypoxia will be exacerbated by eutrophication and may deteriorate with climate change. Long term hypoxia can kill a large number of marine organisms, including clams. Clams are more vulnerable to various adverse environmental factors in an increasingly intensive breeding environment, which increases the risk of disease outbreaks. This is unfavorable for coastal economic development and ecosystem maintenance in China. The respiratory organ of the clam is the gill, and haemolymph transports oxygen and nutrients in the clam. The change in dissolved oxygen directly affects the oxidative stress response and metabolic index in the gill tissue and blood cells. We set up three modes of dissolved oxygen changes to investigate the oxidative stress response and physiological metabolism of R. philippinarum gill tissue and hemolymph in response to dissolved oxygen changes, namely, maintaining normal dissolved oxygen (C treatment), normal dissolved oxygen-acute hypoxia-acute reoxygenation (AHR treatment), and normal dissolved oxygenchronic hypoxia-chronic reoxygenation (CHR treatment). The superoxide dismutase (SOD) activity, catalase (CAT) activity, glutathione peroxidase (GSH-px) activity, malondialdehyde (MDA) content, pyruvate kinase (PK) activity, hexokinase (HK) activity, lactic dehydrogenase (LDH) activity, ATPase activity, proline hydroxylase (PHD) activity, and lipid peroxide (LPO) content of hemolymph and gill tissue under the three modes of dissolved oxygen change were measured using the microplate method with 96 samples. The results showed that the gill tissue of R. philippinarum was the first to respond to the change in dissolved oxygen, and the response was immediate and intense, whereas the response of the haemolymph was delayed and moderate. The oxidation-antioxidant enzyme system of gill tissue and hemolymph changed in a consistent manner, with SOD, CAT, and GSH-px being the most important antioxidative enzymes. SOD and CAT can help to mitigate the damage of dissolved oxygen change on the clam body. The changing trend in oxidative stress and energy utilization systems such as LDH, PK, HK, and MDA is also consistent in gill tissue and hemolymph; PK and HK regulate the efficiency of glycolysis as the dissolved oxygen changes, whereas LDH primarily regulates the efficiency of anaerobic metabolism, and the MDH content reflects the extent of the dissolved oxygen damage to the clam. The enzymes and products involved in physiological metabolism can be used as effective indicators to monitor the response of R. philippinarum to the changes in dissolved oxygen in the living environment. The changes in ATPase activity, PHD activity, and LPO content only show differences among individuals, while the differences are not obvious among different dissolved oxygen modes. The body of R. philippinarum can quickly adjust the oxidative stress and physiological metabolic responses to acute changes in dissolved oxygen, but the response to the chronic changes in dissolved oxygen is slow, resulting in long-term damage to the clam body that is difficult to detect. The results of this study will provide a scientific foundation for adjusting bivalve culture methods and disease prevention methods.