Melatonin (MEL) has potent antioxidant and tissue-protective effects against oxidative stress, so it attracted scientific attention. This study evaluated the effects of MEL on acute pancreatitis (AP) in male rats. Blood samples were collected for assessment of lipid profile, amylase, and lipase activity. Inflammatory cytokines, caspase-3, lipid peroxidation products (MDA), as well as the levels of the antioxidants, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and reduced glutathione (GSH), were measured in pancreatic tissue. AP was proven by histopathological evaluation and by serum elevation of amylase and lipase enzymes. MEL significantly minimized histological alterations of AP, diminished serum amylase, and lipase activity, and improved lipid profile. MEL dramatically reduced MDA levels, stopped the onset of oxidative stress, and maintained SOD, CAT, GPx, and GSH levels in the pancreas of AP rats demonstrating its antioxidant capacity. Additionally, MEL halted the rise in pro-inflammatory cytokines TNF-α, IL-6, and IL-1β. Furthermore, MEL enhanced the anti-inflammatory cytokine IL-10 indicating its anti-inflammatory effect. Finally, it played a cytoprotective role by preventing apoptosis through decreasing elevated levels of caspase-3 and keeping cell viability. In conclusion, MEL has protective effects on the pancreas which are attributed to its anti-hyperlipidemic, antioxidant, and anti-apoptotic effects as well as its anti-inflammatory properties.