Zearalenone (ZEL) is a mycotoxin generated by Fusarium fungus. Ingestion of ZEL-contaminated foods by humans or animals can cause major health concerns. This work assessed the protective role of allicin in mitigating pancreatic damage caused by ZEL in rats. The experimental rats were allocated into control, Allicin (45 mg/kg /day), ZEL (20 mg/kg/ day), and Allicin-ZEL groups. The agents were administered orally for six weeks. ZEL enhanced the serum levels of amylase and lipase, oxidative stress parameters, and endoplasmic reticulum (ER) stress biomarkers, along with a marked decrease in the serum level of insulin. The disturbed architecture of pancreatic acini was demonstrated in the form of vacuolation of acini, degenerated acini with pyknotic nuclei, and infiltration around dilated congested blood vessels, in addition to the presence of dilated intralobular ducts with retained secretions. Also, the islet of Langerhans cells showed vacuolation and darkly stained nuclei. Immunohistochemically, a marked rise in the expression of heat shock protein 70 (HSP70) and P53 and a marked decline in insulin expression were demonstrated. Ultrastructurally, the pancreatic acinar cells and islets of Langerhans cells displayed shrunken irregular nuclei with dilated perinuclear cisternae and dilated rER. Interestingly, co-administration of allicin and ZEL greatly mitigated these detrimental effects. In summary, allicin inhibited pancreatic injury induced by ZEL by decreasing oxidative stress, ER stress, and apoptosis.