Acute pancreatitis is a sudden inflammation of the pancreas that may be life threatening disease with high mortality rates; particularly in presence of systemic inflammatory response and multiple organ failure despite of the conventional antibiotic and symptomatic treatment. Oxidative stress has been shown to be involved in the pathophysiology of acute pancreatitis. This study was designed to investigate the possible effect of pentoxifylline and alpha lipoic acid respectively and in combination on rats with L-arginine induced acute pancreatitis. Rats were divided as follow; Group 1: served as control, Group 2 and Group 3: sacrificed after 24 h and 7 days; respectively, from induction of acute pancreatitis by L-arginine 250 mg/100 g, Group 4 and Group 5: rats treated by pentoxifylline (12 mg/kg) and sacrificed after 24 h and7 days; respectively, from induction of acute pancreatitis, Group 6 and Group 7: treated by alpha lipoic acid (1 mg/kg) and sacrificed after 24 h and 7 days; respectively, from induction of acute pancreatitis, Group 8 and Group 9: treated by pentoxifylline and alpha lipoic acid and sacrificed after 24 h and 7 days; respectively, from induction of acute pancreatitis. Serum samples were collected to assay levels of amylase enzyme, C-reactive protein, IL-6, catalase enzyme activity, malondialdehyde and pancreases were excised for histopathological examination and assay of pancreatic myeloperoxidase. L-arginine induced-acute pancreatitis was evident by increased in serum marker enzymes and by histopathological findings compared to control group. Pentoxifylline and alpha lipoic acid respectively provided protection against L-arginine induced acute pancreatitis possibly by their antioxidant and anti-inflammatory effect. Treatment with alpha lipoic acid exhibited pronounced improvement in the course of pancreatitis when compared to treatment with pentoxifylline. Moreover, the combination of pentoxifylline and alpha lipoic acid offered the most evident protection when compared to groups that received monotherapy; pointing to the effectiveness of such combination therapy.