The aim of the present study was to test biomarker responses in an edible mollusk, Donax trunculus L. (Mollusca, Bivalvia) associated with environmental pollution in the Gulf of Annaba (northeastern Algeria). The biomarkers selected were glutathione S-transferase (GST), acetylcholinesterase (AChE) and metallothioneins (MTs). Samples were collected seasonally (September 2014, and January, April and July 2015) from two sites located over the Gulf of Annaba: El Battah and Sidi Salem. The results obtained reveal that autumn and winter were the two seasons that show an increase in GST activity, an inhibition of AChE activity and a high rate of MT. In addition, a decrease in AChE activity, an increase in both GST activity and MT levels in D. Trunculus collected from Sidi Salem in comparison with those of El Battah were observed. The biomarker responses at the Sidi Salem site reflect the presence of certain pro-oxidative compounds such as metals (Cd, Cu, Pb, Zn, Mn and Fe) determined in sediments in winter (January) 2015. Moreover, metal concentrations, except Fe, were higher at Sidi Salem than at El Battah. Overall, the Gulf of Annaba remains contaminated by heavy metal. However, this metallic contamination is relatively low and the risks for local population via this edible species were also low.