Smoking is a documented risk factor for cancer, e.g., gastric cancer. Nicotine, the principal tobacco alkaloid, would exert its role of contribution to gastric cancer development and progression through nicotinic acetylcholine receptors (nAChRs) and β-adrenergic receptors (β-ARs), which then promote cancer cell proliferation, migration and invasion. As a key isoenzyme in conversion of arachidonic acid to prostaglandins, cyclooxygenase-2 (COX-2) has been demonstrated to have a wide range of effects in carcinogenesis and tumor development. At present, many studies have reported the effect of nicotine on gastric cancer by binding to nAChR, as well as indirectly stimulating β-AR to mediate COX-2-related pathways. This review summarizes these studies, and also proposes more potential COX-2-mediated mechanisms. These events might contribute to the growth and progression of gastric cancer exposed to nicotine through tobacco smoke or cigarette substitutes. Also, this review article has therefore the potential not only to make a significant contribution to the treatment and prognosis of gastric cancer for smokers but also to the clinical application of COX-2 antagonists. In addition, this work also discusses the considerable challenges of this field with special reference to the future perspective of COX-2-mediated mechanisms in development and progression of gastric cancer induced by nicotine.