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The new polyketides lopouzanones A and B, as well as the new 1-<i>O</i>-acetyl and 2-<i>O</i>-acetyl derivatives of dendrodochol B, were isolated from the sponge-derived marine fungus <i>Lopadostoma pouzarii</i> strain 168CLC-57.3. Moreover, six known polyketides, gliorosein, balticolid, dendrodolide G, dihydroisocoumarine, (–)-5-methylmellein, and dendrodochol B, were identified. The structures of the isolated compounds were determined by a combination of NMR and ESIMS techniques. The absolute configurations of the lopouzanones A and B were determined using the Mosher’s method. The cytotoxicity of the isolated compounds against human prostate cancer cells PC-3 and normal rat cardiomyocytes H9c2 was investigated. Gliorosein showed weak DPPH radical-scavenging activity and in vitro cardioprotective effects toward rotenone toxicity and CoCl₂-mimic hypoxia.