Abstract: A drug for antagonizing the replication of porcine reproductive and respiratory syndrome virus (PRRSV) and an application thereof. By using a viral infection test, a drug which antagonizes PRRSV—xanthohumol—is discovered for the first time from among a natural drug library of 386 plant sources. Xanthohumol can effectively inhibit PRRSV replication on both Marc-145 and PAM cells. Five xanthohumol derivatives having different molecular structures are artificially synthesized, and it is discovered that a derivative Xn-4 has the strongest inhibitory effect on virus replication in vitro. Test results of artificial infection and drug therapy in piglets show that the Xn-4 can effectively inhibit PRRSV viremia, relieve clinical symptoms of infected pigs, and significantly reduce lung inflammation and pathological damage.