Honeysuckle stem had been used as feed additives to modulate immunity in breeding industry, which was limited in the aquaculture field. In this study, the immunomodulation of honeysuckle stem ethanol extract (designed as HSE) on Chinese mitten crab Eriocheir sinensis was detected. The crabs fed with HSE diets for 30 days had higher level of the total haemocyte count (HTC), lysozyme activity and PO activity (P < 0.05), and had no obvious affect on the phagocytic activity, NO and TNF-α level. When challenged with Aeromonas hydrophila (1.0 × 107 colony-forming units), HSE exhibited weak antibacterial activity against A. hydrophila and increased survival rate of crabs. The decreasing of THC and the increasing of TNF-α concentration, EsCaspase and EsLITAF mRNA expression level were all inhibited significantly by HSE treatment (P < 0.05), when the crabs were challenged by A. hydrophila. Moreover, the following immune parameters of crabs were enhanced by HSE treatment after A. hydrophila infection, including the rising of phagocytosis index and phagocytic rate of haemocyte, the rising of lysozyme, PO, NOS activities and nitric oxide concentration (P < 0.05). Therefore, it was concluded that HSE had great potential to develop into feed additive of crabs, which could enhance the innate immunity of Chinese mitten crabs E. sinensis effectively after A. hydrophila infection.