The popularity of herbal supplements, especially those with purported anti-inflammatory effects, has drastically increased in recent years as more people have turned to natural therapeutics. As the supplement industry is loosely regulated, the safety and efficacy of these products is poorly understood. In the present study, we examined the effects of natural product formulations prepared by the Biotics Research Corporation (BRC) on cyclooxygenase (COX) enzyme activity. We also evaluated the immune responsiveness of RAW264.7 macrophages, a key cell population involved in the inflammation, to those formulations. As a result, three supplements, BRC-301, BRC-304, and BRC-306, selectively inhibited COX-2, the inducible isoform involved in inflammation. Further evaluation of these three products indicated that BRC-304 and BRC-306 produced minimal effects on the production of inflammatory mediators by lipopolysaccharide (LPS)-stimulated macrophages. BRC-301 decreased the LPS-induced production of nitric oxide and IL-6, as well as CD40 expression. Collectively, these results suggest that the BRC-301 extract, comprising several polyphenolic natural products, may have a protective effect in chronic inflammatory disorders.