Peptic ulcer is one of the world's major gastrointestinal disorders, embracing both gastric and duodenal ulcers, and affecting 10% of the world population. The aim of the current study was to investigate the possible protective effect of tadalafil and pentoxyfilline (PTX) on indomethacin induced peptic ulcer in male wistar rats. Sixty male albino rats were randomly divided into five groups. Control group, ulcerated group. Indomethacin+ Tadalafil, in which animals were pretreated with tadalafil orally for five days before indomethacin. Indomethacin+ PTX, in which animals were pretreated with PTX orally for five days before indomethacin. Indomethacin + combination of two drugs. In indomethacin induced gastric ulceration. Histopathological examination revealed focal coagulative necrosis, atrophy, edema and congestion of blood vessels. Ulcer scoring and ulcer index were markedly increased. Serum levels of Prostaglandin (PGE2) and heme oxygenase-1 (HO-1) were significantly decreased. The ulcerogen also induced marked oxidative stress as evident from the increased malondialdehyde (MDA) and decreased in reduced glutathione (GSH) content. The anti-oxidant activity of superoxide dismutase (SOD) was reduced, while the myeloperoxidase (MPO) content was increased. Gastric nitric oxide (NO) content was apparently decreased and the expression of vascular endothelial growth factor (VEGF) was down regulated while the tumor necrosis factor (TNF-) level was dramatically increased. Pretreatment of ulcerative group by either tadalafil or pentoxyphyllin or their combination improved all these pathological changes. Tadalafil or PTX may have a role in protecting gastric mucosa damage caused by indomethacin which may be useful in the future for treatment of gastric ulceration.