Inflammatory bowel disease (IBD) is a persistent inflammation of the gastrointestinal tract with a significant risk of progression to colorectal cancer (CRC). IBD and CRC have increased cyclooxygenase-2 (COX-2) levels, which is important in these conditions. In IBD, COX-2 contributes to intestinal inflammation, mucosal injury, and immune response dysregulation, while in CRC, it contributes to carcinogenesis and influences tumor microenvironment and angiogenesis. COX-2 may also facilitate its harmful function via prostanoids. Research suggests that COX-2 polymorphisms in IBD and CRC elevate the chance of developing both conditions. Researchers have recognized COX-2 as a biomarker for CRC. Consequently, inhibiting COX-2 may aid in the prevention of IBD and CRC. Non-selective and selective COX-2 inhibitors have demonstrated the ability to mitigate IBD and CRC; however, their efficacy and safety diminish. Nanoparticles, prodrugs, small molecules, and polymeric substrates can deliver COX-2 inhibitors to specific tissues, which makes therapy more effective and safer. Consequently, their application for administering COX-2 inhibitors may herald a new era of improved effectiveness and reduced side effects. Molecular investigations have identified new compounds as potential COX-2 inhibitors. Extracts, microRNAs, and mesenchymal stem cells also help target COX-2 to prevent IBD and CRC.