Objective: Antioxidant, anti-inflammatory, analgesic and antimicrobial activities of Tribulus terrestris (T. terrestris) could be helpful in the treatment of acute pancreatitis; thus, this study was designed to investigate the effects of T. terrestris on cerulein-induced acute pancreatitis in mice. Materials and Methods: Three doses (100, 200 and 400 mg/kg) of T. terrestris hydro-alcoholic extract were administered both orally (60 minutes before pancreatitis induction, p.o.) and intra-peritoneally (30 minutes before pancreatitis induction, i.p.) to different groups of mice (n=6). Pancreatitis was induced by five injections (i.p.) of cerulein 50μg/kg body weight with 1 hr intervals. Animals were euthanized 5 hr after the last injection of cerulein and tissue injures were assessed biochemically and pathologically. Results: T. terrestris extract 200 and 400mg/kg (p.o.) and T. terrestris extract 400 mg/kg (i.p.) reduced pancreatic tissue myeloperoxidase (MPO) activity and serum amylase and lipase levels and alleviated histological parameters. Conclusion: These data suggest that T. terrestris hydro-alcoholic extract was effective in protecting against experimental acute pancreatitis and possibly the efficacy depends on dose and route of administration.