Enterovirus A71 (EV71), coxsackievirus A16 (CVA16), and coxsackievirus B3 (CVB3) are notable pathogens within the Picornaviridae family, responsible for a spectrum of diseases such as severe central nervous system disorders, myocarditis, and pancreatitis. Despite their significant public health burden, no antiviral treatments for these viruses have been clinically approved. In this study, we identified saucerneol, a lignan extracted from Saururus chinensis, as a potent antiviral agent against EV71, CVA16, and CVB3. In vivo experiments demonstrated that saucerneol effectively reduced CVB3 replication in the pancreas and alleviated virus-induced pancreatitis. Mechanistically, saucerneol’s antiviral activity is linked to the elevation of mitochondrial reactive oxygen species (mROS) levels, which are essential for its efficacy. The inhibition of mROS production in vitro significantly reduced saucerneol’s antiviral effects. Furthermore, saucerneol enhanced the phosphorylation of STING, TBK-1, and IRF3 in cells infected with EV71 and CVA16, indicating activation of the STING/TBK-1/IRF3 signaling pathway as a key antiviral mechanism. These findings suggest that saucerneol may serve as a promising natural antiviral compound, offering potential therapeutic benefits against EV71, CVA16, and CVB3 infections, as well as related complications like myocarditis and pancreatitis. Further studies, including clinical trials, are required to evaluate its safety and therapeutic potential for antiviral drug development.