Inflammatory bowel disease (IBD), comprising mainly Crohn’s disease and ulcerative colitis, represents a group of idiopathic, chronic, and relapsing inflammatory disorders of the gastrointestinal tract. These conditions are characterized by a dysregulated immune response to the commensal microbiota in genetically susceptible individuals, leading to epithelial barrier dysfunction and sustained mucosal injury. Reactive oxygen species (ROS) exhibit a quintessentially dichotomous role within the intestinal milieu—while indispensable for antimicrobial defense, host-microbiota communication, and intracellular redox signaling, persistent amplification or deficiency of ROS exacerbates inflammation and cellular damage. Hence, both typical IBD and rare IBD subtypes such as Chronic Granulomatous Disease-associated IBD (CGD-IBD) and certain forms of Very Early Onset-IBD (VEO-IBD) have been connected to dysregulated NADPH oxidase activity. Preclinical mouse models with targeted NADPH oxidase deletions or mutations have improved our understanding of the homeostatic and immunomodulatory roles of NOX/DUOX generated ROS, yet the inherent complexity of the host-microbiome interface and the context-dependent nature of redox signaling in influencing intestinal inflammation and disease progression will necessitate further breakthroughs and new approaches in the future.