Two undescribed bufadienolide glucosides and four undescribed bufadienolides were isolated from the whole plants of Helleborus foetidus (Ranunculaceae). Their structures were determined by extensive spectroscopic analysis and the results of hydrolytic cleavage. The isolated compounds exhibited cytotoxic activities against HL-60 and A549 cells with IC50 values ranging from 0.019 to 3.0 μM. The isolated compounds also showed the Na+/K+ ATPase inhibitory activity. The undescribed compound 16β-formyloxy-10,14-dihydroxy-5β-[(β-d-glucopyranosyl)oxy]-19-norbufa-3,20,22-trienolide induced apoptosis in HL-60 cells through a mitochondria-dependent apoptotic pathway.