Investigation of the constituents of Pycnanthus angolensis roots has resulted in the isolation of four new cyclolignene derivatives, named pycnanthulignene A (1), pycnanthulignene B (2), pycnanthulignene C (3), and pycnanthulignene D (4), and six known compounds, 4,5-dimethoxy-3',4'-methylenedioxy-2,7'-cycloligna-7,7'-diene, 2,7-dimethoxy-3,6-dimethylnaphthalene, 4'-methoxy-4,5-methylenedioxy-2,7'-cyclolign-7-ene, genkwainin, 8-hydroxykanzakiflavone-2, and formononetin. The structures of these compounds were established using spectroscopic methods. Compounds 1 and 3 showed significant antimicrobial activities against a panel of drug-resistant pathogens.