Aim: The present study aimed to investigate the effects of topiramate on pancreatic islets of Langerhans cells in Methotrexate-related pancreatic injury. Materials and Methods: The study was conducted between 04 July - 24 July 2022 in the Animal Research Unit of Recep Tayyip Erdogan University. Male Spraque-Dawley rats were divided into 3 groups with 8 animals in each group. Control group (C) (Only 0.9% saline was administered). A single dose of 20mg/ kg Methotrexate was administered to the MTX group (MTX). The TPM group (TPM) was administered 100 mg/kg/day Topiramate by oral gavage for a total of 14 days, 7 days before and after Methotrexate administration. All subjects were euthanized by anesthesia 16 hours after the last Topiramate dose. Results: We observed widespread edematous areas and necrotic cells in the islets of Langerhans in the MTX. We found that necrotic cells and edematous areas were decreased in the TPM compared to the MTX. We found fewer β cells showing insulin positivity in the MTX compared to the controls (p<0.05). We observed an increase in insulin-positive β-cells in the TPM compared to the MTX (p<0.05). We observed a significant decrease in the number of cells showing glucagon positivity in the MTX compared to the controls (p<0.05). We observed an increased number of α cells showing glucagon positivity in the TPM compared to the MTX (p<0.05). We found that the HDS increased from 0(0-1) in the control group to 6(6-8) in the MTX (p<0.05). It was found as 2(2-3) in the TPM (p<0.05). Conclusion: Our study shows that topiramate has a protective effect on pancreatic islet cells.