Objectives Exposure of Caco-2 cells to indometacin can be a useful model to assess some of the cytotoxic events that appear to underlie the gastrointestinal lesions associated with the use of this anti-inflammatory agent. Using such a cellular model, we addressed here the cytoprotective potential of a recently standardized apple peel polyphenol extract, APPE. Methods We firstly characterized APPE in terms of its free radical scavenging and antioxidant properties, and subsequently investigated its potential to protect Caco-2 cells against the deleterious effects of indometacin on cellular oxidative status (redox state, malondialdehyde, glutathione (GSH) and oxidized glutathione (GSSG) levels), mitochondrial function (ATP and mitochondrial membrane potential) and cell viability (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) reduction and lactate dehydrogenase (LDH) leakage). For comparative purposes, the free radical scavenging properties and reducing capacity of quercetin, epicatechin and rutin were also estimated. Key findings In the absence of APPE, indometacin induced mitochondrial perturbations (reducing ATP and the mitochondrial membrane potential), enhanced the oxidative status (decreasing the GSH/GSSG ratio and increasing dichlorofluorescein oxidation and malondialdehyde) and lowered the cell viability (decreasing MTT reduction and increasing LDH leakage). APPE, whether pre-added or co-incubated with indometacin, concentration-dependently prevented these mitochondrial, oxidative and cell viability alterations. Prompted by the recently recognized ability of indometacin to enhance the mitochondrial formation of reactive oxygen species, APPE was also characterized in terms of its free radical-scavenging capacity. APPE was found to actively scavenge O2·-, HO· and peroxyl radicals. Such free radical-scavenging activity of APPE suggests that its ability to protect mitochondria and prevent the oxidative and lytic damage induced by indometacin arises from its potent antioxidant capacity. Conclusions In Caco-2 cells APPE prevented mitochondrial oxidative and cell viability alterations induced by indometacin possibly through its ability to scavenge reactive oxygen species. These findings are of interest in view of the high prevalence of gastrointestinal side-effects associated with the use of conventional anti-inflammatory agents. © 2010 Royal Pharmaceutical Society of Great Britain.