A considerable body of recent evidence suggests that oxidative stress and exaggerated production of reactive oxygen species play a major role in several aspects of inflammation and shock. Hypericum perforatum is a medicinal plant species containing many polyphenolic compounds, namely flavonoids and phenolic acids. Because polyphenolic compounds have high antioxidant potential, in this study we evaluated the effect of Hypericum perforatum extract on acute pancreatitis induced by cerulein administration in male CD mice. Intraperitoneal injection of cerulein in mice resulted in a severe, acute pancreatitis, which was characterized by edema, neutrophil infiltration, tissue hemorrhage, and cell necrosis as well as increases in the serum levels of amylase and/or lipase in comparison to sham-treated mice. The infiltration of the pancreatic tissue of these animals with neutrophils (measured as increase in myeloperoxidase activity) was associated with expression of the adhesion molecule ICAM-1. Immunohistochemical examination demonstrated a marked increase in the staining (immunoreactivity) for nitrotyrosine and poly(ADP-ribose) (PAR) in the pancreas of cerulein-treated mice in comparison to sham-treated mice. In contrast, the degree of (a) pancreatic inflammation and tissue injury (histological score), (b) expression of ICAM-1, (c) the staining for nitrotyrosine and PAR, and (d) myeloperoxidase activity was markedly reduced in pancreatic tissue sections obtained from cerulein-treated mice administered Hypericum perforatum extract (30 mg/kg, suspended in 0.2 mL of saline solution, o.s.). Moreover, the treatment with Hypericum perforatum extract significantly reduced the mortality rate at 5 days after cerulein administration. Taken together, our results indicate that Hypericum perforatum extract reduces the development of acute pancreatitis.