Background For plastic surgery, ischemia-reperfusion (I-R) injury is a critical problem that results in partial or total flap necrosis. Trimetazidine (TMZ) is a drug used in the treatment of angina pectoris. This study investigated the effect of TMZ on I-R injury in epigastric island flaps using a rat model. Methods Sixteen Sprague-Dawley rats were assigned to two groups, each with eight rats. The sham group comprised of saline-treated rats, while the TMZ group had TMZ-treated rats. An epigastric flap measuring 6 x 4 cm in size was created 30 min after the intraperitoneal administration of either physiological saline or TMZ in both groups. Ischemia was induced on the flaps for 10 h, followed by reperfusion. The flaps were then inset to the original position. Samples were obtained 24 h after reperfusion for biochemical analysis and on day 7 for histopathological analysis. Also, flap survival was evaluated on day 7 using Image-Pro Express. Results The TMZ group had a significantly greater flap survival area compared to the sham group. On histopathological examination, the two groups showed significant differences. The TMZ group had a higher epidermal thickness. On biochemical examination, there were significantly higher levels of malondialdehyde and myeloperoxidase activity in the sham group, while the TMZ group showed significantly greater glutathione and nitric oxide levels. Conclusions In the present study, TMZ administration was found to reduce I-R injury macroscopically, histopathologically, and biochemically in a rat epigastric island flap model. Level of evidence: Not ratable.