Longisglucinol A (<b>1</b>), a polycyclic polyprenylated acylphloroglucinol (PPAP) with a new skeleton, along with two new congeners, longisglucinols B (<b>2</b>) and C (<b>3</b>), were isolated from <i>Hypericum longistylum</i>. Compound <b>1</b> features an unparalleled 6/6/6/5 fused ring skeleton based on a unique 8-oxa-tetracyclo-[8.3.3.0^1,9.0^3,7]cetane core. Longisglucinol A showed remarkable anti-inflammatory activity by inducing macrophage M2 polarization through the suppression of NF-κB.