Physiological and biochemical responses in bivalves exposed to pollutants have proved a valuable tool to assess the health of organisms in aquatic ecosystems. The single and combined effects of mercury (Hg2+, 2 and 10 μg/L) and benzo[a]pyrene (BaP, 3 μg/L) on physiological and biochemical biomarkers in Manila clam, Ruditapes philippinarum were evaluated. Results showed that significant higher oxygen consumption (OR) and ammonia-N excretion rates (NR) together with significant lower ingestion rates (IR) were observed for the 10 μg/L Hg2+ or 3 μg/L BaP treatments compared to controls (P < 0.05). However, clam NR decreased significantly in response to the binary mixtures of 10 μg/L Hg2+ and 3 μg/L BaP (P < 0.05). Moreover, the levels of superoxide dismutase (SOD), catalase (CAT), glutathione-s-transferases (GSTs), glutathione (GSH), acetylcholinesterase (AChE) and malondialdehyde (MDA) in the hepatopancreas of clams were induced substantially, whereas glycogen (GLY) contents were suppressed dramatically after Hg2+ and BaP exposure. Additionally, the integrated biomarker response (IBR) values measured showed significant increases in combination treatments and they were much higher than that in the Hg2+ treatment. This study will provide further information on the defense mechanism in the Manila clam after exposure to marine pollutants and may help evaluate the quality of the aquatic environment.