Introduction: Non-steroidal anti-infl ammatory drugs (NSAIDs), are widely prescribed in clinical practice because of their ability to reduce pain, fever, and infl ammation. However, NSAID-induced gastric mucosal damage is the major side eff ect of these medications. This study aims to reduce gastric mucosal lesions caused by NSAIDs by using pirfenidone by investigating their eff ect on histological, gastric gross mucosal damage. Method: 30 healthy male albino rats were divided into 3 groups each of ten (N=10). A single oral dose of diclofenac sodium (150 mg/kg body weight) was used to induce ulceration for all groups except fi rst. The vehicle (tween 80+NS) was given to the fi rst group, while diclofenac sodium was given to the second group and to all pre-treated groups. The third group were pre-treated with pirfenidone (300 mg/kg). At the end of the experiment, histological examination, and antioxidant and antiinfl ammatory parameters by immunohistochemistry method were evaluated. Results: Diclofenac sodium at a dose (150 mg/kg) produces a signifi cant increment (p > 0.01) in gastric damage score, the expression of tumor necrosis factor-alpha (TNF-α), myeloperoxidase, malonaldehyde, and the ulcer formation percent, compared to the healthy rat’s group. Pirfenidone at a dose of (300 mg/kg) pretreatment in diclofenac induced-ulcer in rats produces a signifi cant reduction (p > 0.01) in gastric damage score, the expression of TNF-alpha, myeloperoxidase, the expression of TNF-alpha, myeloperoxidase, malonaldehyde, and in the ulcer formation percent, yet, less eff ectively than omeprazole and pirfenidone. Conclusion: Diclofenac can be reduced or prevented by the pretreatment of pirfenidone. Pirfenidone showed similar results to the standard treatment (Omeprazole), the protective eff ect of pirfenidone was mainly through their antioxidant and anti-infl ammatory activity by reducing oxidation markers like MPO and MDA, and also reducing infl ammatory cytokines like TNF-alpha