Background and Objective: Morinda citrifolia (MC) commonly known as Noni is being used for many ailments and is considered as wellness drink. It is traditionally used for anti-inflammatory, anti-aging, and immunostimulant properties. The present study has been initiated to investigate the protective effects of MC fruit extract (MCFE) on L-arginine-induced acute pancreatitis (AP) in rats. Materials and Methods: Male Sprague-Dawley rats were randomly divided into groups of control, disease control, positive control, and treatment groups. AP is induced by the administration of a single dose of L-arginine (2 × 2.5 g/kg, intraperitoneally, 1 h apart). Positive control received melatonin (10 mg/kg); treatment groups received 200 mg/kg and 400 mg/kg MCFE 6 days before administration of L-arginine. After 12 h of induction, the serum samples were analyzed for biomarker enzymes such as amylase, lipase, C-reactive protein, superoxide dismutase, glutathione, catalase, tissue nitrate, lactate dehydrogenase, and myeloperoxidase. Histopathological studies and deoxyribonucleic acid (DNA) fragmentation assay were performed from the isolated pancreatic tissue. Results: MCFE administration showed a dose-dependent significant (P < 0.001) protective effect by improving the levels of antioxidant enzymes and reducing the elevated levels of amylase and lipase. The acinar cell damage was limited in histopathological findings and an intact DNA when compared to disease control. Conclusion: MCFE administration showed a protective effect against AP in rats, and it may be due to the attenuation of oxidative stress. Further investigation for the exact molecular mechanism is needed.