(±)-Lucidumone (1), an enantiomeric meroterpenoid possessing an unprecedented skeleton comprising a fused 6/5/6/6/5 polycyclic system, was isolated from Ganoderma lucidum and structurally identified. The absolute configuration of (-)-1 was assigned by single-crystal X-ray crystallography. A plausible biosynthetic pathway for 1 is proposed. A chemical biology approach reveals that (-)-1 selectively inhibits COX-2 by directly binding with an amino acid residue of Tyr385, representing a new structure scaffold of COX-2 inhibitors.