Comprehensive SummaryFour polycyclic ten‐membered lactones possessing unprecedented 10/6/5 tricyclic ring skeleton, named eutypetides A—D (1—4), and an intriguing polyketide containing a hexahydroisobenzofuran‐1(3H)‐one motif, named eutypetide E (5) were isolated from the marine‐derived fungus Eutypella sp. F0219, together with three new related biosynthetic polyketides eutypetides F—H (6—8). The absolute configurations of 1—5 were unequivocally determined by single‐crystal X‐ray diffraction analyses (Cu Kα), modified Mosher's method and electronic circular dichroism (ECD) calculations. Eutypetides G (7) showed remarkable anti‐inflammatory activity and could reduce the mRNA expression of proinflammatory cytokines IL‐1β, IL‐6, TNF‐α, and iNOS induced by LPS. Most notably, compounds 1—4 were formed biogenetically from 6—7 via the key intramolecular [4+2] cycloaddition, while compound 5 could be constructed biogenetically from 8 through the intramolecular [4+2] cycloaddition. All the above eight polyketides are proposed to originate from a C10 and a C6 fatty acid.