Aspertetranones A-D (1-4), four new highly oxygenated putative rearranged triketide-sesquiterpenoid meroterpenes, were isolated from the marine algal-associated fungus Aspergillus sp. ZL0-1b14. On the basis of a comprehensive spectroscopic analysis, the planar structures of aspertetranones were determined to possess an unusual skeleton in the terpenoid part. The relative and absolute configurations of the aspertetranones were assigned on the basis of NOESY analysis, X-ray crystallography, and circular dichroism spectroscopy. Compounds 1-4 were evaluated for anti-inflammatory activity in LPS-stimulated RAW264.7 macrophages. Aspertetranone D exhibited an inhibitory effect against IL-6 production with 69% inhibition at 40 μM.