In the current study, we examined the effects of histamine on survival and immune parameters of the Chinese mitten crab, Eriocheir sinensis. The crabs infected with the common bacteria pathogen Aeromonas hydrophila were injected with 0 µg histamine/g/crab, 1 µg histamine/g/crab, 50 µg histamine/g/crab, or 100 µg histamine/g/crab, and their survival after 96 h was recorded. The results showed that histamine alone had no influence on crab survival but can decrease survival of the crabs challenged with A. hydrophila after 36 h. In addition, the survival of the crabs injected with the high level (100 µg/g) of histamine was significantly greater than that of the lower level (50 µg/g) after 60–96 h (P < 0.05), but not different from that of the control. Immune parameters of the hemolymph in crabs, such as the total hemocyte count (THC), phenoloxidase (PO), acid phosphatase (ACP), alkaline phosphatase (AKP), and superoxide dismutase activity (SOD), were measured at 6 h, 12 h, and 24 h after histamine injection. Some immune parameters, such as PO and SOD, showed an increase, whereas THC, ACP, and AKP levels declined at 6 h. Surprisingly, after the injection of histamine, the crabs quickly released their pereiopods and began to twitch, and the number of the crabs with autotomy and spasm increased with the increasing histamine concentration (P < 0.05). This is the first report that indicates that histamine could lead to crab autotomy. The overall results of this study indicate that the effects of histamine on survival and the immune parameters of E. sinensis infected with A. hydrophila depend on its concentration.