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Witch hazel extracts have been used for decades as cosmetic ingredients in skin care products. Our present study aims to evaluate its potential in anti-pollution products using a previously reported in vitro model. Calcium is a universal second messenger, and we used human respiratory and skin cells to detect changes in intracellular Ca2+ concentrations upon particulate matter contact. Both an increase in pro-inflammatory markers and a decrease in tight junction proteins were confirmed, as previously reported. Witch hazel stem and leaf extract showed significant attenuation of Ca2+ response upon the challenge; it displayed systematic regulations of the signal generator, PAR-2; a pro-inflammatory marker, NF-κB; and a tight junction protein, Occludin. We identified hexagalloylglucose from the extract and concluded that it is a major component regulating protection from particulate matter. Based on these results, witch hazel extract containing hexagalloylglucose is an active ingredient in anti-pollution skin care products.