AbstractAs “non‐cellular organisms”, viruses need to infect living cells to survive themselves. The virus infection must alter host's metabolisms. However, the influence of the metabolites from the altered metabolisms of virus‐infected host cells on virus‐host interactions remains largely unclear. To address this issue, shrimp, a representative species of crustaceans, is challenged with white spot syndrome virus (WSSV) in this study. The in vivo results presented that the WSSV infection enhanced shrimp glycolysis, leading to the accumulation of lactate. The lactate accumulation in turn promoted the site‐specific histone lactylation (H3K18la and H4K12la) in a p300/HDAC1/HDAC3‐dependent manner. H3K18la and H4K12la are enriched in the promoters of 75 target genes, of which the H3K18la and H4K12la modification upregulated the expression of ribosomal protein S6 kinases 2 (S6K2) in the virus‐infected hosts to promote the virus infection. Further data revealed that the virus‐encoded miR‐N20 targeted hypoxia inducible factor‐1α (HIF‐1α) to inhibit the host glycolysis, leading to the suppression of H3K18la and H4K12la. Therefore, the findings contributed novel insights into the effects and the underlying mechanism of the virus‐induced histone lactylation on the virus‐host interactions, providing new targets for the control of virus infection.