•First report on cell-based antioxidant activity of pyranoanthocyanins and other polyphenols of staghorn sumac fruits.•First report on anti-inflammatory effect of pyranoanthocyanins and other polyphenols of staghorn sumac fruits.•First report on potential mechanism of anti-inflammatory effect of staghorn pyranoanthocyanins•Results suggest staghorn sumac or its major components may be beneficial to inflammation related diseases such as IBD. The antioxidant and anti-inflammatory activities of the novel pyranoanthocyanins and other polyphenols from staghorn sumac (Rhus hirta L.) were examined. The results not only confirmed the previously found antioxidant activity by chemical based assays, but more importantly strong anti-inflammatory activity for the first time in cell-based assays. These unique compounds significantly inhibited the production of pro-inflammatory cytokine IL-8 production stimulated by H2O2 and TNF-α. It was also found that these activities of the crude extract were primarily from the individual polyphenols, particularly the unique pyranoanthocyanins and 7-methoxyanthocyanins. Pyranoanthocyanin 1, in particular, showed a markedly strong anti-inflammatory activity at 1 M, followed by pyranoanthocyanin 2 and a 7-methoxyanthocyanin 5. Further mechanism investigation showed that the anti-inflammatory activity was likely mediated through inhibition of NF-κB activation via phosphorylation of IκBα. Results from the present study warrant further investigation into the in vivo anti-inflammatory effect and health benefits using animal models or human subjects.