Background: Acute pancreatitis (AP) is a sudden pancreatic inflammation that has a high mortality rate, especially when associated with systemic inflammation and multiple organ failure. According to reports, cases having acute pancreatitis developed stress ulcers or gastrointestinal mucosal lesions. Nesfatin-1 could control apoptosis and inflammatory effects. Aim: This research is designed to find out the possible protective role of nesfatin-1 on fundic gland mucosal affection in cerulein-induced acute pancreatitis. Methods: Forty rats were splitted into three groups: Group I (control), Group II (induced acute pancreatitis): exposed to cerulein (20 μg/kg, s.c.) five times each separated by one hour, Group III (nesfatin-1 treated): nesfatin-1 (10 µg/kg) is injected intraperitoneally 5 min before the first cerulein adminstration. Results: Acute pancreatitis demonstrated high serum amylase, lipase, IL-1β, and oxidative stress marker (MDA) levels. Fundic gland histological changes secondary to pancreatic injury were confirmed by H&E, immunohistochemical ( IL-1β, CD68), morphometrical, and statistical studies. The fundic glands of Group II showed mucosal disruption and desquamation of the surface epithelial cells. Cells had pyknotic nuclei and vacuolated cytosol aligned parts of the glands, while others were aligned by cells with flattened nuclei. Inflammatory cells were also seen. Many cellular infiltrations and engorged blood vessels were seen. Group III (nesfatin-1 treated) showed results similar to control group. Many fundic mucosal cells in the upper and lower parts had vesicular nuclei and few had darkly stained nuclei. The gastric pits appeared narrow. Conclusions: Nesfatin-1 reduces pancreatic oxidative stress damage and reduces inflammation to decrease AP-induced fundic gland mucosal affection.