The molecular mechanisms leading to inflammatory bowel disease (IBD) are only partially understood. We investigated the role of the transcription factor NFE2L3 in a mouse model of colitis by inducing inflammation using dextran sodium sulfate (DSS). We confirmed the presence of inflammation by histological analysis and elevated levels of the inflammation marker lipocalin-2 (LCN2) in the stool. We found that Lcn2 transcript levels are significantly less elevated in Nfe2l3(-/-) mice than wild type mice. We further showed a reduction of Nfe2l3 mRNA, in wildtype mice upon DSS treatment. We cross referenced ENCODE ChIP data of NFE2L3 binding partners MAFF and MAFK with known IBD and DSS effectors and identified Stat1, Hmox1, and Slc7a11 as potential NFE2L3 targets. These proteins are induced during colitis to suppress the immune response, reduce oxidative stress, and trigger ferroptosis, respectively. We analyzed the candidate targets and observed an increase in their protein expression upon DSS treatment in wild type but not in Nfe2l3(-/-) mice. Furthermore, in the absence of DSS, we observed an increase in the basal levels of pSTAT1 and SLC7A11 proteins in Nfe2l3(-/-) mice. These data suggest that the NFE2L3 transcription factor primes the microenvironment towards a pro-inflammatory ready state during inflammatory bowel disease (IBD).