This work aimed to study the anti-ulcer activity of the combination of the natural product; aqueous anise suspension (Aniseed) with the standard drug misoprostol, against gastric ulcer induced by a non-steroidal anti-inflammatory drug (NSAID); indomethacin, in addition to the possible related anti-oxidant and anti-inflammatory mechanisms. Single oral pretreatment of Aniseed and its combination with misoprostol were given 30 min. before indomethacin induced acute gastric ulceration. The experiment ended four hours later and rat stomachs were tested for the presence of ulcers, then lipid peroxidation, the antioxidant and anti-inflammatory effects were assessed: gastric malondialdehyde (MDA), gastric superoxide dismutase (SOD) activity, and plasma catalase activity, gastric prostaglandin E2 (PGE2), and serum C-reactive protein (CRP) levels. All pretreatments significantly reversed the indomethacin induced increase in ulcer scores, the highest was aniseed combination, followed by misoprostol, then aniseed. Indomethacin produced a significant decrease in gastric SOD activity and PGE2 level, while produced a significant rise in plasma catalase activity and serum CRP level. All pretreatments produced a significant decrease in plasma catalase activity. Pretreatment with the standard drug; misoprostol reversed all the indomethacin induced changes in the biochemical markers. However, misoprostol had no effect on serum CRP level, even after it is combined with aniseed. All pretreatments produced a significant increase in gastric PGE2 level, except for the combination group. The combination was superior to other treatments in its ulcer healing effect, and only ameliorated gastric SOD activity, compared to indomethacin. We concluded that, aniseed combination with misoprostol has a remarkable ulcer healing effect and almost produced a complete protection from gastric ulcers induced by indomethacin, in addition to some additive anti-oxidant effect to misoprostol. Therefore, it is recommended to take anise, while receiving a treatment with misoprostol