Purification of the apolar extracts of the marine sponge Plakinastrella mamillaris afforded the isolation of six new oxygenated polyketides, gracilioethers E–J, featuring an unprecedented oxidation pattern of the polycyclic core. On a common tricyclic core, gracilioethers E, G, and J feature the furanyliden methyl ester substructure and gracilioethers F, H, and I display a γ-lactone substructure. The new structures were elucidated on the basis of extensive spectroscopic (1H and 13C NMR, COSY, HSQC, HMBC, and ROESY), MS, computational and chemical methods. Pharmacological analysis demonstrated that gracilioether H is endowed with in vitro antiplasmodial activity against a chloroquine resistant strain.