4-Hydroxycordoin (1), a natural isopentenyloxychalcone, is a plant secondary metabolite that is relatively rare. Since there are very few reports about the biological activities of 1, its potential benefits for periodontal disease were investigated. A marked and dose-dependent antibacterial activity of 1 was observed against the three major periodontal pathogens, Porphyromonas gingivalis, Fusobacterium nucleatum, and Prevotella intermedia. Moreover, compound 1 showed an antiadhesion effect, since it inhibited attachment of P. gingivalis to oral epithelial cells. Finally, using a macrophage model, the ability of 1 to inhibit the secretion of inflammatory mediators induced by Aggregatibacter actinomycetemcomitans lipopolysaccharide was demonstrated. The anti-inflammatory effect observed was associated with reduced activation of the nuclear factor-κB (NF-κB) p65 and activator protein-1 (AP-1) pathways.