Two new cyclic depsipeptides named swinhopeptolides A (<b>1</b>) and B (<b>2</b>) have been isolated from the marine sponge <i>Theonella swinhoei</i> cf. <i>verrucosa</i>, collected from Papua New Guinea. They each contain 11 diverse amino acid residues and 13-carbon polyketide moieties attached at the <i>N</i>-terminus. Compounds <b>1</b> and <b>2</b> each exist as two conformers in DMSO-<i>d</i><sub>6</sub> due to <i>cis</i>/<i>trans</i> isomerism of the proline residue, and their structures were successfully assigned by extensive NMR analyses complemented by chemical degradation and derivatization studies. Swinhopeptolide B (<b>2</b>) contains a previously undescribed 2,6,8-trimethyldeca-(2<i>E</i>,4<i>E</i>,6<i>E</i>)-trienoic acid moiety <i>N</i>-linked to a terminal serine residue. Swinhopeptolides A (<b>1</b>) and B (<b>2</b>) showed significant inhibition of the Ras/Raf signaling pathway with IC<sub>50</sub> values of 5.8 and 8.5 μM, respectively.