In spite of the beneficial actions of non-steroid anti-inflammatory drugs (NSAIDs) in epithelial inflammation and cancers, their use is limited because of their cyclooxygenase-dependent or independent gastrointestinal toxicity. As an eicosanoid-independent mediator, NSAID-activated gene 1 (NAG-1) has been assessed for its involvement in cellular integrity and pathogenesis in mucosal inflammation and carcinogenesis. At the cellular levels, NAG-1 is involved in the cell growth regulation (cell death, cell cycle arrest, or proliferation) in epithelial and mesenchymal tissues. Moreover, NAG-1 can modulate inflammatory responses in either direct or indirect manner, which ultimately affects fibrogenic and tumorigenic processes in various disease states. Finally, NAG-1 has been assessed for its contribution to cellular behavior, such as the mobility of epithelial and malignant cells in response to the external insults or oncogenic stimulation in the mucosa. This review on the “Yin-Yang” nature of NAG-1-mediated responses provides comprehensive insights into therapeutic and diagnostic interventions for mucosal health and integrity in the human body.