Polygonum cuspidatum (P. cuspidatum) is among the world’s most problematic invasive plant species with negative ecological, socio-economic and security consequences. Management operations in areas invaded systematically generate a large quantity of plant waste, most often without outlets. Using this plant material could constitute a new alternative treatment for sustainable management. P. cuspidatum is well known to have numerous biological properties, containing notably stilbenes, quinones, flavonoids and phenolic acids. The present work proposes a reliable strategy using powerful techniques for the screening and the evaluation of the dermo-cosmetic potential of its aerial parts (AP) and root parts (RP). To the best of our knowledge, only antioxidant and anti-tyrosinase activities were previously evaluated on P. cuspidatum among the targets studied (superoxide dismutase, hyaluronidase, elastase, collagenase and tyrosinase). The results revealed strong antioxidant and anti-collagenase activities, moderate anti-hyaluronidase activity, while weak anti-elastase and anti-tyrosinase activities were observed for ethanolic extracts. Different standards selected and screened on the same targets made it possible to correlate the observed residual activities of produced extracts of P. cuspidatum from Savoie Mont Blanc and their chemical compositions. A structure-activity study was thus conducted on main molecular families, widely represented in the genus Polygonum.