Physiological responses can be used as effective parameters to identify environmentally stressful conditions. In this study, physiology changes such as oxygen consumption, clearance rate, survival in air, condition index and energy reserves were measured on natural populations of cockles collected from different sites at Ria de Aveiro, Portugal. At those sites, sediment samples were collected for Hg concentration analysis. Cockles were used for the evaluation of both the Hg concentration and physiological response. Mercury was detected in the cockle tissue and in the sediment collected from the sampling points both nearby and distant from the main mercury contamination source. The energy content was negatively correlated with both Hg concentration in cockle tissues and survival in air. Nonetheless, the energy content was positively correlated with the condition index, and there was a positive correlation between the survival in air test and the tissue mercury concentration. A PCA-factor analysis explained 86.8% of the total variance. The principal factor (62.7%) consisted of the air survival, the Hg in soft tissues (positive) and the condition index (negative). The second factor (24.1%) consisted of a negative correlation between the oxygen consumption and the clearance rate. Due to their sensitivity to environmental conditions, the physiological responses of cockles can be used to assess the ecological status of aquatic environments. More effort should be invested in investigating the effects of environmental perturbations on cockle health once they are a good reporter organism.