ABSTRACT Grass carp haemorrhagic disease (GCHD), a severe viral affliction caused by grass carp reovirus (GCRV), is responsible for significant mortality among grass carp. Characterised by rapid transmission and latent infections, GCHD poses a critical challenge in aquaculture. Histone acetylation plays a crucial role in gene expression regulation, including key immunology genes. Histone deacetylase‐targeting drugs demonstrate broad‐spectrum disease resistance potential by modulating host immune‐related genes, highlighting their promising role for further exploration and therapeutic development in aquaculture species. In this study, we explore the potential of histone deacetylase inhibitor (HDACi) as a novel antiviral strategy against GCHD. We conducted in vitro and in vivo studies to assess the effects of HDACi on GCRV: trichostatin A (TSA), a traditional HDACi. Our findings revealed that TSA increased the acetylation level of histone 3 in Ctenopharyngodon idella kidney (CIK) cells, inhibiting viral gene expression and reducing the cytopathic effects (CPE) caused by GCRV. Furthermore, transcriptome sequencing elucidated the antiviral mechanisms of TSA, revealing up‐regulation of antiviral‐related genes. Quantitative real‐time PCR (qRT‐PCR) verification confirmed the involvement of the interferon signalling pathway, a key mechanism in the antiviral response to HDACi. In vivo antiviral evaluation demonstrated that intraperitoneal administration of TSA significantly enhanced survival outcomes in grass carp challenged with GCRV. Quantitative analysis revealed TSA treatment substantially suppressed viral replication, as evidenced by reduced viral load measurements. Meanwhile, histopathological examination revealed that TSA alleviated viral‐induced tissue damage. Consistent with the transcriptomic results, TSA enhanced the transcriptional activity of immune‐related genes in the kidney, intestine and brain of grass carp. These findings indicate that HDACi exert a potent antiviral effect against GCRV by modulating host antiviral immune gene expression. Given this host‐directed mechanism, it is plausible that HDACi may pose a lower risk of inducing viral resistance compared to direct‐acting antivirals, highlighting their potential as candidates for new treatments against grass carp haemorrhagic disease.