Porcine reproductive and respiratory syndrome virus (PRRSV) is a persistent pathogen that causes significant economic losses to the global swine industry. Commercial vaccines provide only partial protection, and no effective therapeutic treatments are currently available. In this study, we demonstrate that hesperetin (Hst), a flavonoid glycoside derived from orange and tangerine peels, inhibits PRRSV replication in a dose-dependent manner in Marc-145 and PAMs cells. Transcriptome analysis further reveals that the anti-PRRSV effects of Hst are associated with the suppression of the P38 MAPK pathway, as Hst significantly downregulates key genes, including NRA41, JUN, FOS, and DUSP1. Subsequent investigations show that Hst inhibits PRRSV replication by downregulating the P38/JUN/FOS signaling cascade. These findings offer valuable insights for the development of novel preventive and therapeutic strategies against PRRSV infection.