Climate change is producing sea level rise and deoxygenation of the ocean, altering estuaries and coastal areas. Changes in oxygen availability are expected to have consequences on the physiological fitness of intertidal species. In this work we analyze the coping response of the intertidal stout razor clam (Tagelus plebeius (Lightfoot, 1786)) to extreme environmental changes in oxygen concentration. Their biochemical responses to normoxia, hypoxia, and hyperoxia transition at different intertidal level (low–high) were measured through an in situ transplant experiment. The high intertidal level negatively affected the analyzed traits of the T. plebeius populations. The differences in reactive oxygen species production, total oxyradical scavenger capacities, and catalase activity also suggested more stressful conditions at the high level where long-term hypoxia periods occur. Both hypoxia and re-oxygenation provoked re-adjustments in the antioxidant responses and higher lipid oxidative damage (normoxia < hypoxia < re-oxygenation). The observed responses in transplanted clams at the opposite intertidal level suggested the potential acclimation of T. plebeius to cope with new environmental conditions. These findings are discussed within a global changing context where both increasing deoxygenation conditions and sea level rise are predicted to be exacerbated in the area driven by climate change.