Oxygen availability in water is considered one of the most important factors for growth and productivity in aquatic submerged macrophytes. In the present study, the growth, stress responses, and metabolic changes in Potamogeton anguillanus Koidz. (Potamogetonaceae) were assessed after a 21-day exposure to low (hypoxia; dissolved oxygen, DO < 1 mg/L) or null (anoxia) oxygen concentrations in water. High growth rates and an increased indole acetic acid (IAA) content in P. anguillanus were observed under the hypoxic conditions (4-fold to control) compared to the anoxic conditions. In addition, the activation of glycolysis and fermentation processes was further recorded, given the increase in alcohol dehydrogenase activity and pyruvate concentration on the studied plants that were exposed to low oxygen concentrations. Moreover, the positive correlations of antioxidative enzyme activities, catalase (CAT) and guaiacol peroxidase (POD) with hydrogen peroxide (H2O2) confirmed the species ability to scavenge excess H2O2 under low oxygen stress. The capillary electrophoresis–mass spectrometry (CE-MS) analysis of the metabolome identified metabolite accumulations (e.g., glutamate, glutamine, aspartate, asparagine, valine, malate, lactate, citrate, isocitrate, proline and γ-amino butyric acid) in response to the anoxia.