Introduction: The conventional drugs for inflammatory bowel disease (IBD) have many side effects that impact patient's quality of life, leading to the emergence of alternative therapies such as pomegranate peel ethanol extract (PPE). This study aims to investigate the anti-inflammatory effect of PPE by observing TNF-α expression in mice induced chronic inflammation of the colon using dextran sodium sulfate (DSS). Methods: 28 Swiss Webster mice samples were taken and divided into five groups, the control group (6 mice), the negative control group (5 mice), the group that was given DSS and aspirin (6 mice), the group was given DSS and a high dose of PPE (5 mice), and the group was given DSS and a low dose of PPE (6 mice). In mice, distal colonic tissue was taken and then stained immunohistochemically against TNF-α and observed with light microscopy at 400x magnification, and TNF-α expression was assessed using the H-Score. Results: TNF-α expression was significantly lower in the group given a high dose of PPE than the negative control group (p <0.05), with mean rank scores of 3.00 and 8.00. There was no significant difference between the group given PPE with a high dose and aspirin (p> 0.05). Conclusion: TNF-α expression in colonic epithelial cells of mice given DSS decreased upon treatment of a high dose of PPE, indicating a mechanism of decreasing inflammation. PPE also has the same effect as aspirin in reducing inflammation.