A large body of evidence indicates that genetic mutations, epigenetic changes, chronic inflammation, diet, and lifestyle are key risk factors for colorectal cancer (CRC). Prevention of CRC has long been considered a plausible approach for the population and individuals at high risk for developing this disease. A significant effort has been made in the development of novel drugs for both prevention and treatment over the past two decades. This review highlights recent advances in our understanding of the role of nonsteroidal anti-inflammatory drugs in CRC prevention and adjuvant treatment. Moreover, we focus on the molecular mechanisms underlying the antitumor effects of these drugs in CRC. The knowledge of how anti-inflammatory agents inhibit cancer formation and progression may provide a rationale for the development of more effective chemopreventive and chemotherapeutic agents with less toxicity.