The purpose of this study is to investigate the effect of montelukast on lipopolysaccharide (LPS)-induced pancreatitis. Adult male Wistar rats were divided into 5 groups: normal control, control montelukast, LPS group, and two LPS + montelukast-treated groups. Acute pancreatitis (AP) was induced by a single dose of LPS (6 mg/kg, i.p.), while montelukast was given in two different doses (10 and 20 mg/kg/day) for 3 consecutive days prior to the injection of LPS. AP was demonstrated by significant increases in serum levels of lactate dehydrogenase (LDH) and pancreatic enzymes lipase and amylase. Proinflammatory response activation was evident by elevated serum levels of nitric oxide (NO) and increased pancreatic concentrations of tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1β), and intercellular adhesion molecule-1 (ICAM-1). The activity of myeloperoxidase (MPO), a neutrophil infiltration marker, has also been increased. Oxidative stress was confirmed by significant increases in the concentrations of lipid peroxides measured as thiobarbituric acid reactive substances (TBARS) and decreases in the concentrations of reduced glutathione (GSH) in the pancreatic tissues of animals treated with LPS. Histological examination confirmed the biochemical alterations. Montelukast treatment reversed all these biochemical indices and histopathological changes that LPS induced. Montelukast reduced the increase in serum levels of lipase, amylase, LDH, total nitrite/nitrate, TNF-α, IL-1β, and ICAM-1. MPO activities and TBARS concentrations were also suppressed while GSH content was increased in pancreatic tissues. These results show that montelukast may be a beneficial pharmacological agent in protection against LPS-induced oxidative pancreatic injury by inhibiting neutrophil infiltration, counteracting oxidative stress, and suppressing inflammatory mediators.