Hypoxia stress is a key environmental stressor that can induce white spot syndrome virus (WSSV) outbreaks, but underlying mechanisms remain unclear. Here, transcriptome analysis and RT-PCR were conducted to investigate the impact of acute hypoxia stress on gene expression profiles in shrimp. We revealed that acute hypoxia stress significantly altered the expression profile of genes in shrimp gill, particularly downregulating genes encoding chitin-binding proteins (CBPs), including Mucin-19, GAAP, CP1114, SgAbd-1, pro-Resilin, Obstructor-E, CP, GP1, and AMP1A. Downregulation of Mucin-19, GAAP, CP1114, and SgAbd-1 by RNA interference significantly increased shrimp mortality and viral loads following WSSV infection. Temporal expression analysis further confirmed that Mucin-19, GAAP, CP1114, and SgAbd-1 were involved in WSSV infection. Thus, acute hypoxia stress facilitates WSSV infection by inhibiting CBPs expression. This study provides the first evidence of the role of shrimp CBPs in response to hypoxia stress and antiviral defense, offering novel insights into environmental stress-host-virus interactions.