Fitness and survival of an organism depend on its ability to mount a successful stress response when challenged by exposure to damaging agents. We hypothesized that co-exposure to contaminants may exacerbate oxidative stress in hypoxia-challenged benthic animals compromising their ability to recover upon reoxygenation. This was tested using the amphipod Monoporeia affinis exposed to hypoxia followed by reoxygenation in sediments collected in polluted and pristine areas. In both sediment types, oxygen radical absorbance capacity (ORAC) and antioxidant enzyme activities [superoxide dismutase (SOD) and catalase (CAT)] increased during hypoxia, suggesting that M. affinis has a strategy of preparation for oxidative stress that facilitates recovery after a hypoxic episode. Exposure to contaminants altered this anticipatory response as indicated by higher baselines of ORAC and SOD during hypoxia and no response upon reoxygenation. This coincided with significantly elevated oxidative damage evidenced by a marked reduction in glutathione redox status (ratio of reduced GSH/oxidized GSSG) and an increase in lipid peroxidation (TBARS levels). Moreover, RNA:DNA ratio, a proxy for protein synthetic activity, decreased in concert with increased TBARS, indicating a linkage between oxidative damage and fitness. Finally, inhibited acetylcholinesterase (AChE) activity in animals exposed to contaminated sediments suggested a neurotoxic impact, whereas significant correlations between AChE and oxidative biomarkers may indicate connections with redox state regulation. The oxidative responses in pristine sediments suggested a typical scenario of ROS production and removal, with no apparent oxidative damage. By contrast, co-exposure to contaminants caused greater increase in antioxidants, lipid peroxidation, and slowed recovery from hypoxia as indicated by CAT, GSH/GSSG, TBARS and AChE responses. These results support the hypothesized potential of xenobiotics to hamper ability of animals to cope with fluctuating hypoxia. They also emphasize the importance of understanding interactions between antioxidant responses to different stressors and physiological mechanisms of oxidative damage.