Porcine reproductive and respiratory syndrome virus (PRRSV) causes significant economic losses to the swine industry worldwide. Despite numerous studies on this virus, the molecular mechanisms underlying PRRSV infection remain unclear. Enhancer of mRNA decapping 3 (EDC3) is a crucial scaffold protein for P-body assembly that stimulates mRNA decapping by alleviating self-inhibition of the DCP1/2 decapping complex. In this study, we investigated the impact of EDC3 on PRRSV proliferation, as well as its influence on three key adaptor proteins of the innate immune system: Toll-like receptor interleukin-1 receptor domain-containing adaptor inducing interferon-β (TRIF), mitochondrial antiviral signaling protein (MAVs), and myeloid differentiation factor 88 (MyD88). Western blotting and quantitative real-time PCR assays showed that EDC3 overexpression in both Marc-145 and PAM-CD163 cells significantly inhibited transcription of the PRRSV N gene and expression of the N protein. Conversely, knockdown of EDC3 expression in these cells significantly promoted the transcription of the PRRSV N gene and expression of the N protein. Furthermore, our results demonstrated that EDC3 overexpression significantly enhanced the expression of MyD88, whereas the inhibition of EDC3 expression led to a reduction in this process. In contrast, EDC3 did not effectively promote the increase in protein levels of TRIF and MAVs. In conclusion, the P-body EDC3 protein suppresses PRRSV proliferation and function by upregulating MyD88. This work is the first to report the mechanism of action of EDC3 against PRRSV, providing ideas for studying antiviral innate immunity.