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Viruses have evolved sophisticated strategies to evade host immune defenses, often targeting conserved signaling pathways. In shrimp, the NF-κB signaling pathway is crucial for antiviral immunity, yet its regulation during White Spot Syndrome Virus (WSSV) infection remains poorly understood. Here, we identify and characterize wsv100, an immediate-early (IE) protein of WSSV, as a key antagonist of the NF-κB pathway. wsv100 interacts directly with the transcription factor Dorsal, preventing Dorsal phosphorylation by Pelle kinase. This inhibition suppresses Dorsal’s nuclear translocation and downstream expression of antimicrobial peptides (AMPs), essential for antiviral defense. Knockdown of wsv100 reduced WSSV replication, increased Dorsal phosphorylation, and enhanced AMP expression, leading to higher survival rates in infected shrimp. Conversely, wsv100 overexpression promoted WSSV replication and AMPs suppression. These findings reveal a novel immune evasion mechanism by which WSSV subverts the NF-κB pathway and highlight the evolutionary arms race between hosts and viruses. This study enhances our understanding of host-virus interactions and offers potential targets for antiviral strategies in shrimp aquaculture.