Seven undescribed meroterpenoids, peniscmeroterpenoids A - G, were isolated from the marine-derived fungus Penicillium sclerotiorum GZU-XW03-2. Their structures were established by the spectroscopic methods and the electronic circular dichroism (ECD) calculations. Peniscmeroterpenoid A possessed an unprecedented and highly oxidized 6/7/6/5/5 pentacyclic system, featuring a unique tetrahydrofuro [2,3-b]furan-2(3H)-one motif. Peniscmeroterpenoids B - E owned rare 6(D)/5(E) fused rings were not common in natural products, and peniscmeroterpenoid E is the first example of a berkeleyone analogue stripped of the methyl ester fragment. In bioassays, peniscmeroterpenoids A and D inhibited the production of nitric oxide (NO) in RAW264.7 cells with IC50 values of 26.60 ± 1.15 and 8.79 ± 1.22 μM. Moreover, peniscmeroterpenoid D significantly suppressed the production of pro-inflammatory mediators (COX-2, IL-1β and IL-6) and the protein expression of the enzyme iNOS.