Cyclooxygenase-2 (COX-2) is involved in the production of prostaglandins and thromboxanes, which control biological processes like inflammation, angiogenesis, and cell division. Numerous premalignant tissues and many human malignant tumors overexpress COX-2. Metabolites from COX-2 may support tumor growth, transformation, invasion, metastatic dissemination, premalignant hyperproliferation, downregulation of apoptosis, and tumor survival. COX-2 also triggers activity like cancer stem cells (CSCs). Populations of CSCs isolated from many cancer types are linked to overexpression of COX-2. Using nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of solid tumors, including colon, stomach, and esophageal malignancies. The anticancer potential of NSAIDs is mediated via COX-2 dependent or COX-2 independent pathways. For cancer patients, COX-2 may be a crucial target for therapeutic and chemoprotective measures. This review introduces the involvement of COX-2 in cancer via different pathways and provides a comprehensive review of the most recent updates on COX-2 inhibitors as potential anticancer candidates. This review aims to spark fresh thinking in the pursuit of more logical COX-2 inhibitor designs that may effectively treat cancer.