Marine macroalgae have evolved a different mechanism to maintain physiological concentrations of essential metal ions and non-essential metals. The objective of the present work was to evaluate the antioxidant response and DNA damage of copper and cadmium ions in three halophytes, namely, Acanthophora spicifera, Chaetomorpha antennina, and Ulva reticulata. Accumulation of copper was significantly higher (P < 0.05) than that of cadmium. Biochemical responses showed that copper was considerably more toxic than cadmium (P < 0.05). Decreases in glutathione content and fluctuations of super oxide dismutase, catalase, and glutathione peroxidase activities were observed corresponding to time and concentration of exposure. Interestingly, it was also observed that antioxidant levels decreased as a result of metal accumulation, which may be due to free radicals generated by copper and cadmium in seaweeds. The present study also showed that copper and cadmium increased oxidative stress and induced antioxidant defense systems against reactive oxygen species. The order of toxicity for metals in the studied seaweeds was U. reticulata > A. spicifera > C. antennina. DNA damage index analysis supported that copper was significantly (P < 0.05) more toxic than cadmium. Bioaccumulation, biochemical responses, and DNA damage observed in the here analyzed marine macroalgae after exposure to selected metals indicate that these marine organisms represent useful bioindicators of marine pollution.