In the present study, the oxidative stress and antioxidant response in hepatopancreas of the black tiger shrimp Penaeus monodon under desiccation stress were studied, such as activities of antioxidant enzymes (SOD, CAT, GPx and POD), oxidative damage to lipid and protein which indexed by contents of LPO, MDA, protein carbonyl (PC) and ROS production, and the expression of HSP70 and ferritin gene. The duration of desiccation significantly influenced the shrimp survival, and the mortality rates were 10% and 55.0% after desiccation 0.5 h and 3 h, respectively. Compared with the control group, after exposed to desiccation stress, the content of LPO, MDA, PC and ROS production in hepatopancreas increased significantly. SOD, CAT and POD activity in hepatopancreas increased significantly at 0.5 h, but decreased markedly at 1 h. GPx activity in hepatopancreas increased significantly at 0.5 h and 1 h, then decreased significantly at 3 h. The transcript levels of HSP70 and ferritin gene in hepatopancreas increased significantly at 1 h. HE staining showed that desiccation induced damage symptoms in hepatopancreas of P. monodon. These results revealed that desiccation could induce oxidative stress and antioxidant response via confusion of antioxidant enzymes activity and gene transcript level in hepatopancreas of P. monodon, and the time of shrimp under desiccation should lower than 0.5 h.