To explore the response mechanism of digestion and immune system to “reverse back syndrome” (RBS) of Babylonia areolata, both healthy(control group, CG) and disease samples (early stage of RBS [ERBS], middle stage of RBS [MRBS], and late stage of RBS [ERBS]) were collected, the Vibrio content, the activity of SOD, POD, CAT, ACP, AKP, LZM, pepsin, lipase and amylase in these samples were detected by TCBS plate count methods and enzyme test kit methods. The results showed that the content of Vibrio increased significantly with the development of the disease, and it reached the maximum in LRBS of Babylonia areolata. In MRBS, the activity of POD, AKP and LZM increased, and significantly higher than CG and ERBS; compared with ERBS, the activity of CAT, SOD, ACP, pepsin and lipase decreased; but compared with CG, the CAT and ACP activity increased significantly, and the pepsin and lipase activity decreased significantly, while there was no significant difference in SOD and amylase activity. In LRBS, the activities of digestive enzymes and immune-related enzymes were lower than those in MRBS, and compared with CG, the POD and ACP activity significantly increased, the pepsin, lipase and amylase activity significantly decreased, while there was no significant difference in the CAT, SOD, AKP and LZM activity. In conclusion, the immune system and digestive system are involved in the immune response during the outbreak of Vibrio in the RBS, and the CAT, POD and ACP activity can be used as the detection and evaluation indicators.