Four 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 ma-rine-derived fungus Eutypella sp. F0219, together with three new related biosynthetic polyketides eutypetides F−H (6−8). The abso-lute configurations of 1−5 were unequivocally determined by single-crystal X-ray diffraction analyses (Cu Kα), and electronic circular dichroism (ECD) calculations. Eutypetides G (7) showed remarkable anti-inflammatory activity and could reduce the mRNA expres-sion of proinflammatory cytokines IL-1β, IL-6, TNF-α, and iNOS induced by LPS. Most notably, compounds 1, 2, and 5 were formed bi-ogenetically from 6−8 via the key intramolecular [4+2] cycloaddition, respectively.