Herbal extracts have been considered as ideal alternative to antibiotics in aquaculture and application of combinatory effective extracts always can exhibit the enhanced bioactivity with high efficiency. In our study, a novel herbal extract combination GF-7, which is composed ofGalla Chinensis,Mangosteen Shellextracts as well as the effective parts ofPomegranate peelandScutellaria baicalensisGeorgi extracts, was prepared and applied for the therapy of bacterial infection in aquaculture. The HPLC analysis of GF-7 was also investigated for quality control and chemical identification. In the bioassay, GF-7 had excellent antibacterial activity against various aquatic pathogenic bacteriain vitro, and the related MIC values were between 0.045 and 0.36 mg/mL. After feedingMicropterus salmoidewith GF-7 (0.1, 0.3, and 0.6%, respectively) for 28 days, the activities of ACP, AKP, LZM, SOD, and CAT of the liver in each treatment group were significantly increased and the content of MDA was significantly decreased. Meanwhile, the hepatic expression of the immune regulators includingIL-1β,TNF-α, andMyd88at different times was up-regulated in varying degrees. The challenge results exhibited a good dose-dependent protective effect onM. salmoidesinfected withA. hydrophila, which was further confirmed by liver histopathology. Our results imply that the novel combination GF-7 is a potential natural medicine for the prevention and treatment of numerous aquatic pathogenic infectious diseases in aquaculture.