Muscadine skins and seeds of two varieties were analyzed for total phenolic content and antioxidant ability. Extracts were then screened for abilities to directly inhibit hyaluronidase activity in vitro. Hyaluronidase is an enzyme responsible for the depolymerization of hyaluronic acid, a major component of the extracellular matrix of soft connective tissues including the synovial membrane and fluid. Its activity is implicated in inflammatory diseases such as osteoarthritis, facilitating the degradation of cartilage, and stimulating further inflammatory mediators. Similarly, a variety of sorghum brans versus other common grain brans were tested for total phenolic content, antioxidant activity, and anti-hyaluronidase activity in vitro. In other studies, extracts of muscadine skin, seed and pomace, and Polygonum cuspidatum, an herb rich in trans-resveratrol, were screened for anti-inflammatory activity in vivo. In the phorbol myristate (TPA) inflamed mouse ear edema model, markers of both acute and chronic inflammation were measured after treatment with each test extract. Finally, muscadine skin extracts were tested for the ability to decrease inflammation in the trinitrobenzene sulfonic acid (TNBS) colitis model in rats. Results: Hyaluronidase activity was inhibited by both muscadine seed and skin fractions. The seed fraction was 2-3 times more potent than skins on a wt/wt basis. Hyaluronidase activity in both correlated directly with total phenolics and antioxidant activity of the extracts. Sorghum bran inhibited hyaluronidase more potently than other bran. Sumac sorghum bran had the greatest inhibitory activity. Inhibition again correlated with total phenolics and antioxidant activity in each bran. Commonly used wheat and rice bran had weak inhibitory activities relative to the high phenolic containing grain sorghum brans. In the TPA model of ear inflammation, extracts of muscadine skin, seed, and combination treatments significantly reduced ear edema, ear biopsy weight and polymorphonuclear infiltration compared to TPA vehicle control. Polygonum cuspidatum extract also inhibited both acute and chronic inflammation in the TPA model in a dose-dependent manner, and was more potent than trans-resveratrol when tested at comparable doses. In the TNBS model of colitis, muscadine-enriched diets decreased neutrophil invasion into the colonic tissue, edema and macroscopic scores. Inflammation in the colon was eliminated in rats receiving the muscadine enema treatment. In these, TNBS produced no significant changes in markers from healthy animals. Conclusions: Muscadine grape skin/seed, sorghum bran, and Polygonum cuspidatum extracts have high total phenolics, high antioxidant abilities, and are highly anti-inflammatory in both in vitro and in vivo screening systems. These qualities support use of these bioactive botanicals and/or their fractions in functional food, nutraceutical and cosmeceutical products.