Porcine reproductive and respiratory syndrome virus (PRRSV) remains one of the most important pathogens, resulting in huge economic losses to the global pig industry. Ipriflavone is an isoflavone derivative involved in various biological processes, showing anti-inflammatory, anti-apoptotic, antioxidant, and neuroprotective effects. However, the role of ipriflavone in antiviral immune response to PRRSV is unknown. In this study, we discovered that ipriflavone could significantly inhibit PRRSV replication. Moreover, ipriflavone inhibited PRRSV replication regardless of whether ipriflavone was added pre-, co-, or post-PRRSV infection, and ipriflavone mainly inhibited virus replication and assembly stages. Importantly, ipriflavone had the capacity to upregulate the expression levels of IFN-β and ISG56. Additionally, ipriflavone promoted the expression of RIG-I and MAVS, and induced phosphorylation of IRF3 and STAT1, while reducing PRRSV replication. Collectively, ipriflavone could enhance the RIG-I/IRF3 signaling pathway, thereby inhibiting PRRSV replication. These findings will provide an important theoretical basis for the development of therapeutic agents against PRRSV infection.