Herqupenoid A (1), a sesquiterpene-quinone hybrid with an unparalleled 5/5/6/5-fused ring skeleton based on a multicyclic caged 2,7-dioxatetracyclo[5.4.0.04,11.05,9]hendecane fragment, was isolated from fungus Penicillium herquei. Its structure was assigned by extensive spectroscopic analyses, DP4+ computational method, and single-crystal X-ray diffraction. Further pharmacology research has established that compound 1 exhibited significant anti-inflammatory activity via inhibiting NF-κB-NLRP3 axis with an IC50 value of 2.63 μM, which was stronger than the positive control dexamethasone. A putative biosynthetic pathway involving the key hemiacetal and aldol condensation reactions for 1 was also discussed.