Chemical investigation of the marine-sponge-derived fungus Penicillium adametzioides AS-53 resulted in the identification of two new bisthiodiketopiperazine derivatives, adametizines A (1) and B (2), from cultivation in a liquid potato-dextrose broth (PDB) culture medium, whereas two new acorane sesquiterpenes, adametacorenols A (3) and B (4), were isolated from a rice solid culture medium. The structures of these compounds were elucidated on the basis of spectroscopic analysis. The absolute configuration of compound 1 was determined by X-ray crystallographic analysis, and that of 3 was determined by modified Mosher's method. Compound 1 exhibited lethality against brine shrimp (Artemia salina) with an LD50 value of 4.8 μM and inhibitory activities against Staphyloccocus aureus, Aeromonas hydrophilia, Vibrio spp. V. harveyi and V. parahaemolyticus, and Gaeumannomyces graminis with minimum inhibitory concentration values of 8, 8, 32, 8, and 16 μg/mL, respectively. Chlorination at C-7 significantly increased the brine shrimp lethality and antimicrobial activity of the bisthiodiketopiperazines.