Three dihydrostilbenes belonging to the polyphenol pool characterized in the leaves of Sicilian liquorice (Glycyrrhiza glabra L.) have been tested for their antioxidant and anti-inflammatory activity. The three dihydrostilbenes (PA-82, GA-23, DO-07) were in vitro tested to evaluate their capability to scavenge the stable radical 1,1-diphenyl-2-picrylhydrazyl (DPPH), and to decrease thromboxane B2 (TxB2) and prostaglandin E2 (PGE2) release in human whole blood samples. On the basis of the observed capability of these compounds to affect the cell COX-1/COX-2 pathway, a molecular docking study was carried out in order to understand in detail the ability of these compounds to bind to COX-1 and COX-2. The results show that the liquorice dihydrostilbenes are preferred ligands for COX-2 rather than for COX-1, providing a good rational for the observed selectivity in ex vivo experiments. Therefore, they appear to be good candidates for employment in human therapy against inflammation-related pathological conditions.