Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway plays an important role in antiviral immunity. This research reports the full-lengthDOMEreceptor gene inPenaeus monodon(PmDOME) and examines the effects ofPmDOMEandPmSTATsilencing on immune-related gene expressions in shrimp hemocytes during white spot syndrome virus (WSSV) infection.PmDOMEandPmSTATwere up-regulated in shrimp hemocytes upon WSSV infection. Suppression ofPmDOMEandPmSTATshowed significant impacts on the expression levels ofProPO2(melanization),Vago5(interferon-like protein) and several antimicrobial peptides, includingALFPm3, Penaeidin3, CrustinPm1andCrustinPm7. Silencing ofPmDOMEandPmSTATreduced WSSV copy numbers and delayed the cumulative mortality caused by WSSV. We postulated that suppression of the JAK/STAT signaling pathway may activate the proPO, IFN-like antiviral cytokine and AMP production, resulting in a delay of WSSV-related mortality.