The present study was performed to analyze the bioaccumulation of heavy metals, biochemical constituents, antioxidants, and metabolic enzymes in the crab Scylla serrata from different regions of Tuticorin, Southeast Coast of India. The study area consists of Threspuram and Harbour Beach which were polluted environments due to the discharge of industrial effluents and domestic sewage into them. Punnakayal, which is a low-polluted environment where the in-situ culture of S. serrata is carried out by local fish farmers, was selected as well. The results revealed that the level of heavy metals, biochemical constituents, antioxidants, and metabolic enzymes were significantly high in the crabs collected from Threspuram and Harbour Beach compared to the crabs collected from Punnakayal. This study indicates that crabs from polluted environments have significant heavy metals bioaccumulation which leads to elevated antioxidants and metabolic enzyme levels. This implies that the crabs are under oxidative and metabolic stress.