Five new highly oxygenated eremophilane-type sesquiterpenoids, possessing C19 (1 and 2), C15 (3 and 4), and C14 (8) skeletons, along with eight known eremophilenolides were obtained from the aerial parts of Ligularia sagitta. The absolute configuration of 1 was assigned by X-ray diffraction analysis and that of 3 by ECD spectroscopy. Compounds 1-10 were evaluated for their antibacterial activities against Staphyloccocus aureus, Bacillus subtilis, Escherichia coli, Bacillus cereus, and Erwinia carotovora. Compounds 4 and 5 displayed broad-spectrum inhibitory activity against these bacteria with MIC values of approximately 7.25 μg/mL, followed by 3 and 6 with MIC values in the range of 23.0-125.0 μg/mL. Compounds 3 and 8 showed mild activity against three human tumor cell lines (IC50 ≈ 13 μM). Preliminary structure-activity relationships for these eremophilenolides are reported.