It is well known that administration of non-selective cyclooxygenase (COX) non-steroidal anti-inflammatory drugs (NSAIDs) increases the risk of developing gastric and duodenal ulcers. Previously, we reported that administration of indomethacin, one of these COX non-selective drugs, results in acute inflammation of the small intestine and that the subsequent increased release of cytokines, such as interleukin-6 and tumor necrosis factor-α, and histamines can lead to the development of dry skin. However, the effect of indomethacin administration in aging mice remains unknown. We aimed to investigate the effect of indomethacin administration on the small intestine of 40-week-old adult mice. As a result, both macroscopic and histologic abnormalities were observed in their small intestines. Expression of diamine oxidase, a histamine-degrading enzyme in the jejunum, was also decreased. In addition, expressions of mucin-2 and zonula occludens-1, both of which regulate the intestinal barrier function, were also decreased. Therefore, it was suggested that administration of indomethacin to aging mice may cause the release of histamines, which consequently increase in concentration in the small intestine, infiltrate into the blood, and circulate throughout the body as the intestinal barrier function declines.