Two new sesterterpenoids sesterchaetins A and B (1 and 2) and two new polyketides chaetoketones A and B (3 and 4) were characterized from the culture extract of a deep sea-sediment-derived fungal strain Chaetomium globosum SD-347. Their structures including absolute configurations were unambiguously solved by detailed NMR, mass spectra, and X-ray crystallographic analysis. Compounds 1 and 2 contained a characteristic 5/8/6/5 tetracyclic carbon-ring-system, which represented rarely occurring natural product frameworks. The new isolates 1–4 exhibited selective antimicrobial activities against human and aquatic pathogenic bacteria and plant-pathogenic fungi.