Understanding the potential effects of chlorogenic acid (CGA) isomers on the intestinal epithelium is important because coffee intake exposes consumers to the six major CGA isomers: 3-caffeoylquinic acid (3-CQA), 4-caffeoylquinic acid (4-CQA), 5-caffeoylquinic acid (5-CQA), 3,4-dicaffeoylquinic acid (3,4-diCQA), 3,5-dicaffeoylquinic acid (3,5-diCQA), and 4,5-dicaffeoylquinic acid (4,5-diCQA). The present study determined the relative effects of CGA isomers on the antioxidant status of inflamed Caco-2 intestinal cells by investigating the oxidative-stress-responsive pathway and nuclear-factor-erythroid-derived-2-like 2 (Nrf2) signaling. Differentiated Caco-2 cells were challenged with the inflammatory mediators PMA and IFNγ, as a model of intestinal inflammation in vitro. Significant redox ( p < 0.05) responses to these mediators were assessed by indirect measurement of induced generation of reactive oxygen species (ROS), as well as the expression of reduced (GSH) and oxidized (GSSG) glutathione. This translated to a 40% reduction in the GSH/GSSG ratio. We found that responses in these parameters were associated with increased Nrf2 activation ( p < 0.05). ROS generation and increased IL-8 secretion were found in challenged cells, indicating an association between induced oxidation and inflammatory status. Oxidative stress was ameliorated by CGA isomers, which scavenged intracellular ROS, increased GSH, and activated Nrf2 signaling. diCQA isomers were relatively more effective at reducing IL-8 ( p < 0.05). The observed increase in Nrf2 signaling led to upregulated expression of some Nrf2 target genes ( GPX2, KEAP1, and NFE2L2) in Caco-2 cells and activated the Nrf2-Keap1-ARE-signaling pathway. These findings indicate that CGA isomers present in coffee have bioactivity toward alleviating oxidative stress associated with intestinal inflammation.