Polyphenols are natural compounds with high structural diversity whose common occurrence in plants renders them intrinsic dietary components. They are known to be secondary metabolites characterized by a wide spectrum of biological activities, and a growing body of evidence indicates they have anti-inflammatory potential. It is well known that inflammation plays a key role in many chronic diseases such as circulatory diseases, pulmonary diseases, autoimmune diseases, diabetes, cancer, and neurodegenerative diseases. Polyphenols influence the inflammatory process by controlling and inhibiting pro-inflammatory cytokines such as IL-1β, IL-6, IL-8, and TNF-α, and cyclooxygenase-2 (COX-2) enzyme involved in the metabolism of arachidonic acid. Furthermore, polyphenols exhibit anti-inflammatory activity on many levels via NF-κB inhibition, and MAPK, iNOS, and growth factors regulation. This paper reviews the current state of knowledge concerning the potential of various dietary polyphenols to inhibit the effects of COX-2 in colon cancer, by examining the available evidence regarding the efficacy and safety of these compounds obtained from in vitro and animal studies.