Non-steroidal anti-inflammatory drugs (NSAIDs) are primarily used for the treatment of acute or chronic conditions with pain and inflammation. Evidence from a wide range of sources suggested that chronic administration of NSAIDs reduced the risk of cancer incidences. Both the epidemiological and animal studies showed an inverse association between the incidence of various cancers and the use of aspirin or other NSAIDs. The chemopreventive and therapeutic interventions of NSAIDs in cancer are obvious; however, the instigation of drug and treatment period depends on the study objective. Typically, prevention involves initiating the medication before the appearance of clinical symptoms and lasts long-term; while treatment could be short-term and contingent to the response of patient to the medication. Recent studies from our laboratories provided substantial evidence on the anti-cancer activity of tolfenamic acid, a NSAID for the potential applications in pancreatic, esophageal and lung cancers. In this review, we provide a summary on the potential benefits of NSAIDs in a variety of human cancers with more emphasis on tolfenamic acid.