<p>Porcine reproductive and respiratory syndrome virus (PRRSV) is widely prevalent and causes significant economic losses to the global swine industry. Currently available vaccines provide insufficient protection, and there are no clinically approved antiviral treatments specifically targeting PRRSV. Accordingly, developing safe and potent measures for PRRS prevention and control remains an urgent priority. Yinhuang soluble powder is a traditional Chinese medicinal preparation mainly composed of baicalin and chlorogenic acid, with baicalin serving as its principal active ingredient, which demonstrates significant potential in antiviral research. However, current research on baicalin’s anti-PRRSV activity is notably lacking, with its molecular mechanisms still not fully elucidated. In this study, in vitro experiments demonstrated that both Yinhuang soluble powder and baicalin not only effectively inhibited PRRSV replication but also interfered with the viral replication cycle, concurrently demonstrating significant downregulation of pro-inflammatory cytokines. Network pharmacological screening identified eight core targets of baicalin against PRRSV, namely MAPK14, MAPK10, MAPK8, NF-κB1, MAPK1, SRC, IL-6, and TP53. Molecular docking revealed baicalin’s strong binding affinity to the core targets, with free binding energies below − 7.0&#xa0;kcal/mol. In addition, metabolomics identified 29 metabolites associated with the anti-PRRSV effects of baicalin, the main components of which were glycerophospholipids, glycerolipids, and fatty acyls, and the principal metabolic pathways through which baicalin exerts its anti-PRRSV effects are glycerophospholipid and glycerolipid metabolism. In conclusion, this study demonstrates that baicalin exhibits promising anti-PRRSV efficacy, proposing new insights for PRRS prevention and treatment.</p>