Four new azaphilones, sclerotiorins A–D (1–4), as well as the dimeric sclerotiorin E (5) of which we first determined its absolute configuration, and 12 known analogues (5–16) were isolated from the fermentation broth of Penicillium sclerotiorum OUCMDZ-3839 associated with a marine sponge Paratetilla sp.. The new structures, including absolute configurations, were elucidated by spectroscopic analyses, optical rotation, ECD spectra, X-ray single-crystal diffraction, and chemical transformations. Compounds 11 and 14 displayed significant inhibitory activity against α-glycosidase, with IC₅₀ values of 17.3 and 166.1 μM, respectively. In addition, compounds 5, 7, 10, 12–14, and 16 showed moderate bioactivity against H1N1 virus.