The aim of this study was to examine pancreatic lesions and the possible prophylactic effects of agomelatine (AGO) in lipopolysaccharide (LPS)-induced sepsis in rats. Twenty-four female, 1-year-old Wistar albino rats were divided into three groups: group I (control), group II (study group; 5 mg/kg LPS i.p., single dose), and group III (treatment group; LPS + AGO, single dose p.o., 20 mg/kg AGO + 5 mg/kg LPS, 30 minutes after AGO treatment). The rats were sacrificed six hours after LPS administration. At the necropsy, blood and pancreatic tissue samples were collected for biochemical, pathological, and immunohistochemical analyses. The results showed that LPS caused an increase in serum amylase and lipase levels and a decrease in glucose levels. Histopathological analysis revealed infiltration of numerous neutrophils in pancreatic interstitial tissue and in vessels. In addition, slight vacuoles indicating degenerative changes were observed in endocrine and exocrine pancreatic tissues. Increased caspase-8, haptoglobin (Hp), IL-4, and IL-10 and decreased SIRT-1 expression was observed in both endocrine and exocrine parts of the pancreas in the LPS group. AGO ameliorated the biochemical, histopathological, and immunohistochemical findings. The present study results revealed that LPS-induced pancreatic damage to both endocrine and exocrine cells. In contrast, AGO had ameliorative effects on both biochemical and pathological findings in rats.