Bioassay-guided fractionation of the combined fruits, leaves, and twigs (fruiting branches) of Callicarpa americana, collected from a plot in a forested area in southern Florida, led to the isolation of six new clerodane diterpenes (1−6) and eight known compounds. The structures of 1−6 [12(S),16ξ-dihydroxycleroda-3,13-dien-15,16-olide (1), 12(S)-hydroxy-16ξ-methoxycleroda-3,13-dien-15,16-olide (2), 12(S)-hydroxycleroda-3,13-dien-15,16-olide (3), 16ξ-hydroxycleroda-3,11(E),13-trien-15,16-olide (4), 3β,12(S)-dihydroxycleroda-4(18),13-dien-15,16-olide (5), and 12(S)-hydroxycleroda-3,13-dien-16,15-olide (6)] were elucidated by interpretation of spectroscopic data and chemical methods. The absolute configuration at C-12 in 1 and 3 was ascertained using the Mosher ester technique. The cytotoxicity of all isolates was tested against a panel of human cancer cell lines, and compounds 1, 4, and 6, and the known compounds genkwanin, 16ξ-hydroxycleroda-3,13-dien-15,16-olide, and 2-formyl-16ξ-hydroxy-3-A-norcleroda-2,13-dien-15,16-olide were active (ED50 <5 μg/mL). However, 1 was found to be inactive against human cancer cells implanted in mice using a hollow-fiber tumor model.