Pollution and climate change can induce oxidative stress (OS) in aquatic organisms. Reduced activity or incoordination between antioxidant enzymes in marine bivalves may cause cellular impairment with effects on higher levels of ecological organization. The present study aims to assess the condition factor and the activity of antioxidant enzymes catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione-S-transferase (GST), and glutathione concentration (GSH) in soft tissues of Donax trunculus (Linnaeus, 1758) as indicators of the state of marine ecosystems along the Bulgarian Black Sea coast. The wedge clams were sampled manually from different localities in June and in September. The activity of antioxidant enzymes and GSH concentrations varied both seasonally and among localities. Higher values of GSH, SOD and GPx were registered in wedge clams collected in autumn compared to those collected in summer. In wedge clams higher activity of the major phase II detoxification enzyme GST was observed in summer at localities with intensive tourism, suggesting an activation of the cell detoxification processes, presumably in response to increased environmental pressure. In conclusion, the observed presence of elevated enzyme activities suggested activation of the antioxidant protection system of the wedge clams in response to environmental pressure, indicating their ability to cope with induced OS and adapt to local conditions, and thus maintain ecosystem health.