Objectives: To investigates the mucoprotective effect of genistein on gastric injury in rats with indomethacin (IMN)-induced gastropathy. Methods: Male Sprague-Dawley rats were randomly divided into three groups. Group 1 (control; n = 6) was given distilled water (DW). Group 2 (IMN; n = 6) was given indomethacin (IMN) 150 mg/kg dissolved in 5% sodium bicarbonate (NaHCO3-) 1 mL/rat via intragastric tube at time 0 and 4 h. Group 3 (genistein; n = 6) was given genistein 100 mg/kg dissolved in 0.1% dimethyl sulfoxide (DMSO) plus IMN 150 mg/kg at time described as group 2. Four hours after the second dose, the stomach was removed to examine iNOS western blot expression, malondialdehyde (MDA), and histopathologic examination. Serum was collected to determine TNF-alpha and prostaglandin E2(PGE2) levels using ELISA technique. Results: Tissue MDA and serum TNF-alpha were significantly increased in the IMN group, as compared to the control group (9.70 ± 0.40 vs. 1.56 ± 0.14 nmol/mg protein, P = 0.000; 210.28 ± 0.98 vs. 126.4 ± 0.13 pg/mL, P = 0.000, respectively) and decreased in the genistein group when compared to the IMN group (2.87 ± 0.37 vs. 9.70 ± 0.40 nmol/mg protein, P = 0.000; 156.59 ± 0.10 vs. 210.28 ± 0.98 pg/mL, P = 0.000, respectively). Serum PGE2level in IMN group was decreased significantly compared with control group (152.83 ± 0.10 vs. 303.33 ± 2.16 pg/mL, P = 0.000) and increased in the genistein group compared to the IMN group (247.65 ± 0.01 vs. 152.83 ± 0.10 pg/mL, P = 0.000). Expression of tissue iNOS was increased in the IMN group and improved in genistein groups. Most of the rats in the IMN group developed moderate to severe gastric erosion and ulcers. Gastric erosions and neutrophil infiltration score were significantly decreased in the genistein group. Conclusions: Genistein attenuated IMN-induced gastropathy in rats by reducing inflammation, decreasing oxidative stress, restoring mucoprotective function, and improving gastric histopathology.