Antibacterial-activity-guided fractionation of a dichloromethane extract from the fruit of <i>Cordyline manners-suttoniae</i> and subsequent structure-activity investigations resulted in the identification of 10 new (<b>1</b>-<b>10</b>) and one known (<b>11</b>) 5α-spirostane saponin. The structures of the new compounds were established by 1D and 2D NMR analyses. The absolute configurations of the isolated compounds were determined by X-ray diffraction analysis or chemical derivatizations. The most active compound, suttonigenin F (<b>6</b>), inhibited the Gram-positive bacteria <i>Staphylococcus aureus</i> with MIC<sub>75</sub> values that were comparable to those of the antibiotic chloramphenicol. Structure-activity relationships were also obtained from the assessment of antibacterial and cytotoxic activities of the isolated saponins.