Abstract: In order to develop a herbal compound medicine for the prevention and treatment of skin ulcer syndrome (SUS) in the sea cucumber Apostichopus japonicus, we screened single herbs with significant inhibitory effects on Vibrio splendidus from a pool of 14 herbs. The most promising antimicrobial herbal compound, FF-Z (comprising Terminalia chebula, Rhus chinensis, Andrographis paniculata, and Ligusticum chuanxiong in a ratio of 15 g﹕2 g﹕10 g﹕5 g), was optimally selected using an orthogonal experiment. Subsequently, 420 healthy sea cucumbers were randomly divided into 7 groups: Negative control group (NC group, normal feed), Positive control group (PC group, normal feed), Enrofloxacin control group (En group, feed containing enrofloxacin powder at 20 g/kg), and four FF-Z treatment groups (with feed containing FF-Z at 10, 20, 30, and 40 g/kg, respectively). Following ten consecutive days of feeding, V. splendidus dip bath with a final concentration of 10⁷ CFU/mL was administered to all groups except the NC group. The results showed that V. splendidus exhibited high sensitivity to the herbal compound FF-Z, with an inhibition circle diameter reaching (23.10±0.62) mm and MIC and MBC values of 7.81 and 15.63 mg/mL, respectively. Sea cucumbers in all FF-Z dosage groups significantly increased (P<0.01) activities of SOD, ACP, and AKP, surpassing those of the En group. Following V. splendidus infection, the onset of SUS in the FF-Z dosage groups occurred 2d later than that in the NC group. Moreover, the final incidence rates of SUS in the 20, 30, and 40 g/kg FF-Z groups were 22.08%, 22.14%, and 14.58%, respectively, which were lower than that in the PC group (84.45%). Pathological tissue section analysis showed that the addition of FF-Z at 30 g/kg effectively reduced inflammatory reactions caused by pathogenic bacteria invasion into infected tissues, thereby protecting sea cucumber tissues. The study demonstrates that the herbal compound FF-Z enhances immunity and disease resistance in sea cucumber, providing effective prevention and protection against skin ulcer caused by V. splendidus. It retards the morbidity process and reduces the SUS morbidity rate.