Background Gastric ulcer is a very common gastrointestinal disease that may be dangerous and even may lead to death. The current study was conducted to detect the prophylactic effects of agomelatine on indomethacin-induced gastric ulcer. Methods In this study, a total of 5 groups were created as the sham, ulcer, omeprazole, agomelatine 1 mg/kg and agomelatine 5 mg/kg groups. The effects of agomelatine on indomethacin-induced gastric injury were investigated. Total antioxidant and oxidant levels; the oxidant parameters like oxidative stress index and the inflammation markers such as tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6 and interleukin-10 levels in stomach tissue were determined by ELISA. In addition, the gastric mucosal injury occurred in stomach wall was examined with histopathological methods. Results While the levels of the inflammatory markers, total oxidant status and oxidative stress index increased at an obvious level especially in the indomethacin group, the total antioxidant status levels decreased. It was observed that these parameters were improved at a significant level in agomelatine 1 mg/kg and agomelatine 5 mg/kg groups when compared to ulcer group; and the results were similar to omeprazole group. It was also observed that our histopathological findings were consistent with all our other results. Conclusions The results of this study showed that agomelatine usage in indomethacin-induced gastric ulcer model provides beneficial results.