Acute pancreatitis (AP) is a severe inflammatory disorder for which effective treatments are currently lacking. Cirsilineol (CSL), a flavonoid derived from Artemisia plants, is recognized for its potent anti-inflammation and antioxidant characteristics. The mechanisms underlying AP and potential therapeutic agents remain unknown. This study investigates the effects of CSL on AP and delves into its underlying mechanism. Our results indicate that CSL significantly improved cell viability in AR42J pancreatic acinar cells and influenced the levels of pro-inflammatory cytokines. Furthermore, CSL markedly decreased apoptosis markers and inhibited the Nuclear Factor kappa-B (NF-κB) activation by reducing phosphorylation of p65 and inhibitor of NF-κB alpha (IκBα). These findings underscore the powerful anti-inflammatory and anti-apoptotic properties of CSL, acting through the NF-κB pathway, indicating its promise as a therapeutic option for AP.