The blood clam is being developed into a model bivalve molluscs for assessing and monitoring marine pollution on the offshore seabed. However, the information on the response of blood clam to PAHs, an organic pollutant usually deposited in submarine sediment, remains limited. Herein, we employed multiple biomarkers, including histological changes, oxidative stress, neurotoxicity and global DNA methylation, to investigate the effects of Bap exposure under laboratory conditions on blood clams and its potential mechanisms. Acute Bap exposure can induce significant morphological abnormalities in gills as shown through hematoxylin-eosin (H.E) staining, providing an intuitive understanding on the effects of Bap on the structural organization of blood clams. Meanwhile, the oxidative stress was significantly elevated as manifested by the increase of antioxidants activities of superoxide dismutase (SOD), catalase (CAT), peroxidase (POD) and glutathione-s-transferase (GST), lipid peroxidation (LPO) level and 8-hydroxy-2’-deoxyguanosine (8-OHdG) content. The neurotoxicity was also strengthened by Bap toxicity manifested as inhibited acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) activities. In addition, the global DNA methylation level was investigated, and a significant DNA hypomethylation was observed in Bap exposed blood clams. The correlation analysis showed that the global DNA methylation was negatively correlated with antioxidants (SOD, CAT and POD) activities, but positively correlated choline enzymes (AChE and ChAT) activities. These results collectively suggested that acute Bap exposure can cause damage in gills structures in blood clams possibly by generating oxidative stress and neurotoxicity, and the global DNA methylation was inhibited to increase the transcriptional expression level of antioxidants genes and consequently elevate antioxidants activities against Bap toxicity. These results are hoped to shed some new light on the study of ecotoxicology effect of PAHs on marine bivalves.