Neutrophils are essential for microbial defense but can aggravate tissue damage by prolonged recruitment and activation. The complexity of neutrophil involvement in chronic inflammation underscores our limited understanding of how their adaptation and reprogramming in tissues influence disease progression. Here, we demonstrate that neutrophils recruited in acute inflammatory bowel disease (IBD), chronic granulomatous disease-associated IBD, and in murine colitis and infection models undergo rapid and extensive transcriptional reprogramming in the intestine, resulting in the emergence of DUOX2 NADPH oxidase expression. Functional studies utilizing neutrophil-specific DUOX2-inactivated mice reveal critical and dichotomous roles of DUOX2 in promoting inflammation during colitis while protecting against intestinal infection. Neutrophils with active DUOX2 amplify and prolong inflammatory responses, contributing to a more proinflammatory milieu in the intestine. These findings unveil a niche-directed reprogramming of neutrophils that orchestrates the immune response during inflammation, presenting a novel and promising target for therapeutic development in IBD.