The stability of an apple peel polyphenol extract (APPE) with powerful antioxidant activity was evaluated under acidic conditions in vitro, and its protective effect against gastrointestinal damage was investigated in rats treated with indomethacin. The antioxidant activity of APPE remained stable at pH 2.0 for 4 h. In rats treated with indomethacin (40 mg/kg ig), the previous administration of APPE protected the gastric, intestinal, and colonic mucosa from oxidative stress by preventing increased malondialdehyde concentrations and decreasing the GSH/GSSG ratio. APPE also displayed anti-inflammatory effects by preventing neutrophil infiltration in the mucosa, as evidenced by the lower myeloperoxidase activity. These protective effects of APPE resulted in the prevention of macro- and microscopic damage and of barrier dysfunction along the gastrointestinal tract of the indomethacin-treated animals. This study supports the concept that apple peel polyphenols may be useful in the prevention and/or treatment of nonsteroidal anti-inflammatory drug-associated side effects.