The native species Ruditapes decussatus and the invasive species Ruditapes philippinarum have an important ecological role and socio-economic value, from the Atlantic and Mediterranean to the Indo-Pacific region. In the aquatic environment, they are subjected to the presence of different contaminants, such as mercury (Hg) and its methylated form, methylmercury (MeHg). However, few studies have assessed the impacts of Hg on bivalves under environmental conditions, and little is known on bivalve oxidative stress patterns due to Hg contamination. Therefore, this study aims to assess the Hg contamination in sediments as well as the concentration of Hg and MeHg in R. decussatus and R. philippinarum, and to identify the detoxification strategies of both species living in sympatry, in an aquatic system with historical Hg contamination. The risk to human health due to the consumption of clams was also evaluated. The results obtained demonstrated that total Hg concentration found in sediments from the most contaminated area was higher than the maximum levels established by Sediment Quality Guidelines. This study further revealed that the total Hg and MeHg accumulation in both species was strongly correlated with the total Hg contamination of the sediments. Nonetheless, the THg concentration in both species was lower than maximum permissible limits (MPLs) of THg defined by international organizations. R. decussatus and R. philippinarum showed an increase in lipid peroxidation levels along with the increase of THg accumulation by clams. Nevertheless, for both species, no clear trend was obtained regarding the activity of antioxidant (superoxide dismutase, catalase) and biotransformation (glutathione S-transferase) enzymes and metallothioneins with the increase of THg in clams. Overall, the present work demonstrated that both species can be used as sentinel species of contamination and that the consumption of these clams does not constitute a risk for human health.