The bivalves have capability to accumulate the toxicant substances as heavy metals in their body tissues, therefore, they might be used as a good bio-indicators of water contamination. The present work aimed to measure the concentration of Cd, Cu, Pb, Mn, and Zn in the soft tissues of Ruditapes decussatus which collected between December 2018 and February 2019 from two sites of Mediterranean Sea. One from Alexandrian Port (Site I) and the other from Port Said (Site II), Egypt, as well as to estimate the potential physiological change of the clam affected by these pollutants. Samples from Site I gives comparatively higher water salinity and metals concentration in soft tissues. The statistical analysis shows significant increase in the level of malondialdehyde (MDA) while superoxide dismutase (SOD) and glutathione peroxidase were found decreased in the R. decussatus soft tissue collected from Site I. The correlation coefficient of physicochemical parameters, heavy metals and oxidative stress biomarkers in Site I shows that glutathione peroxidase and superoxide dismutase have positive correlation with acetylcholinesterase (r=0.912) and (r=0.929), respectively. SOD, on the other hand, was having negative correlation with MDA (r= -0.886). The reported values in this study are considered as basic data in monitor of the anthropogenic activities in future along the coast, as well as it is starter point in assessment of pollution that maybe effect on the aquatic organisms in the Mediterranean marine environment.