Since their sessile lifestyle, mussels are particularly vulnerable to environmental stressors, including those linked to oxygen fluctuations. To investigate the putative time-dependent influence of water hypoxia on physiological and biochemical responses of mussels, specimens of Mytilus galloprovincialis were exposed to 4 and 10 days of water hypoxia (DO at 2.5 mg L-1). Gills and digestive gland (DG) were used to evaluate the oxidative status in terms of lipid peroxidation and protein oxidation, and the expression and the activity of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT). Moreover, in DG, cell viability and cell response to volume changes were analysed. We found that, after 10-days hypoxia, lipid peroxidation increased in both DG and gills, while no changes in protein oxidation were observed. In the DG, exposure to both 4 and 10 days of hypoxia was accompanied by an enhancement of both SOD transcriptional levels and activity. In the gills, only an increase in the enzyme expression was observed after 10 days of treatment. In contrast, CAT gene expression and activity remained stable across tissues and treatments. Overall, these responses point to a tissue-specific and time-dependent modulation of both oxidative status and antioxidant defences in mussels challenged by hypoxic stress.