Grass carp reovirus (GCRV) belongs to the family of reoviridae, which mainly causes hemorrhagic disease in grass carp, with high morbidity and mortality rate, which seriously affects the efficiency of grass carp aquaculture, and at present, there is no effective treatment and new varieties of disease-resistant species. Capsid-targeted viral inactivation (CTVI) is a potent antiviral strategy based on the formation of fusion proteins between viral coat proteins and exogenous proteins, whereby the fusion proteins are integrated into the virus upon viral invasion and assembly, and the exogenous proteins directly disrupt and degrade the viral DNA/RNA to provide antiviral efficacy. The aim of this paper was to explore the potential application of CTVI in rare minnow infested with GCRV, to provide a theoretical basis for the breeding of new varieties of grass carp resistant to hemorrhagic disease. We used heat shock protein 70 (HSP70) as promoter, combined with Tgf2 transposon, assembled GCRV outer capsid protein VP3 and Staphylococcus aureus nucleases (SN) to form a fusion protein VP3-SN, constructed a Tgf2-based anti-hemorrhagic disease system (THVS) and a transgenic model of rare minnow, and investigated the apoptotic and immune responses of transgenic rare minnow in resistance to GCRV infection by HE and TUNEL staining, CAT and NO detection, and qPCR. Apoptosis, inflammation and immune responses in transgenic rare minnow against GCRV infection. The results showed that the transgenic rare minnow would limit GCRV amplification during GCRV infection, further affect oxidative stress and reduce the expression of TLR4-MYD88-NF-kB pathway, apoptosis-related genes (BCL2, Caspae3) and inflammation-related genes (IL-1β, TNFα), showing strong GCRV resistance. This experiment provides a theoretical basis and rationale for breeding new grass carp varieties resistant to hemorrhagic disease.