Colitis associated cancer (CAC) is a chronic inflammation driven colon cancer among individuals with Inflammatory Bowel Disease. Its development is associated with the inflammation-dysplasia-carcinoma pathway which differs from the adenoma-carcinoma pathway of sporadic colon cancer (CRC). Matrix Metalloproteinases are zinc-dependent endopeptidases against extracellular matrix proteins expressed in the gastrointestinal tract during inflammation. We have shown that Matrix Metalloproteinase 9 (MMP9) plays a protective role in CAC contrary to its inflammatory role in acute-colitis. I hypothesize that epithelial-derived MMP9 mediates tumor suppression in CAC by regulating genomic stability via Notch1 activation. This study identifies the role of epithelial derived-MMP9 in CAC via “MMP9-Notch1-ARF-p53 axis” pathway which regulates apoptosis, cell-cycle arrest and DNA damage. This study also identifies the role of epithelial-derived MMP9 in maintaining genomic stability by reducing reactive oxygen species and activating mismatch repair mechanisms. Thus, MMP9 expression could potentially be a natural way to suppress inflammation induced colon cancer.