The link between chronic inflammation and cancer involves cytokines and mediators of inflammatory pathways. Cyclooxygenase-2 (COX-2), a key enzyme in fatty acid metabolism, is upregulated during both inflammation and cancer. COX-2 is induced by pro-inflammatory cytokines at the site of inflammation and enhanced COX-2-induced synthesis of prostaglandins stimulates cancer cell proliferation, promotes angiogenesis, inhibits apoptosis, and increases metastatic potential. As a result, COX-2 inhibitors are a subject of intense research interest toward potential clinical applications. Epidemiological studies highlight the potential benefits of diets rich in phytonutrients for cancer prevention. Plants contain numerous phytonutrient secondary metabolites shown to modulate COX-2. Studies have shown that these metabolites, some of which are used in traditional medicine, can reduce inflammation and carcinogenesis. This review describes the molecular mechanisms by which phytonutrients modulate inflammation, including studies of carotenoids, phenolic compounds, and fatty acids targeting various inflammation-related molecules and pathways associated with cancer. Examples of pathways include those of COX-2, mitogen-activated protein kinase kinase kinase, mitogen-activated protein kinase, pro-inflammatory cytokines, and transcription factors like nuclear factor kappa B. Such phytonutrient modulation of COX-2 and inflammation continue to be explored for applications in the prevention and treatment of cancer.