Indomethacin is a well known non steroidal anti-inflammatory drug. It exerted many side effects including acute gastritis. Melatonin is a strong antioxidant. The protective role of melatonin against indomethacin-induced gastritis was a point of controversy. Misoprostol is a synthetic prostaglandin (PGE1). Many literatures stated conflicting observations concerning the prophylactic effect of misoprostol against indomethacin-induced gastritis. The purpose of the present study was planned to assess the prophylactic role of the administration of melatonin, misoprostol or both versus the indomethacin-induced acute gastritis. Thirty-five adult male albino rats were fasted for 24 hours before drug ingestion to assure the full effect and dose of each drug. The rats were segregated into two major groups: GI: sham control group: further subdivided into (A, B and C) and G П: indomethacin-treated group: further subgrouped into (A, B, C and D).Subgroup IA: received normal saline through gastric gavage tube.Subgroup IB: received melatonin (60 mg/kg bw) through gastric gavage tube.Subgroup IC: received misoprostol (50μg/kg bw) through gastric gavage tube.Subgroup IIA: received indomethacin (48mg/kg bw) through gastric gavage tube.Subgroup IIB: received indomethacin and melatonin in the preceded doses through gastric gavage tube.Subgroup IIC: received indomethacin and misoprostol in the preceded doses through gastric gavage tube.Subgroup IID: received indomethacin, melatonin and misoprostol in the preceded doses through gastric gavage tube.The rats were sacrificed 4 hours after drug ingestion. The body region of the stomach was selected and examined by magnifying lens to calculate the ulcer index then it was examined by the light microscope. Histomorphometric study was done using the image analyzer computer system to calculate the mean of the area percentage of the connective tissue, the mean of the optical density of the PAS reaction and the mean of the area percent of the stem cells.The study revealed that indomethacin caused high ulcer index, extensive destruction of the mucosa, observable lymphocytic infiltration. There was scanty amount of connective tissue, mucous secretion and proliferating stem cells.In the group receiving indomethacin and melatonin, there was improvement of the morphology of the gastric mucosa in the form of: significant decrease of the ulcer index, infrequent foci of superficial erosions surrounded by normal mucosa associated with decrease of the lymphocytic infiltration. The amount of connective tissue, the volume of mucous secretion and the number of the proliferating stem cells were increased. In the group receiving indomethacin and misoprostol, there was observable improvement of the morphology of the gastric mucosa in the form of: high significant decrease of the ulcer index, almost normal gastric mucosal architecture, increased thickness of the mucous secreting cell layer. The amount of connective tissue, the volume of mucous secretion and the number of the proliferating stem cells were markedly increased. In the group receiving indomethacin, melatonin and misoprostol, there was marked improvement of the morphology of the gastric mucosa more than that observed when administering each drug alone. This was manifested by: very high significant reduction of the ulcer index and almost normal gastric mucosal architecture. The amount of connective tissue, the volume of mucous secretion and the number of the proliferating stem cells were markedly increased more than the preceding groups. The study was supported by statistical analysis which showed significant results when comparing the different parameters of subgroups IIB, C and D to subgroup IIA and IA.In conclusion, indomethacin induces morphological and histomorphological injuries to the gastric body mucosa of rats. Melatonin has a partial protective role against indomethacin-induced gastritis, misoprostol has a more protective effect in indomethacin-induce-gastritis while using both drugs in combination, resulted in effective protection against indomethacin -induced gastric lesions more than each drug alone.