Objective. To evaluate the hypolipidemic activity and antiatherosclerotic effect of polysaccharide of Polygonatum sibiricum (PPGS), which is a kind of Chinese herbal medicine using the rhizome part of the whole herb. Materials and Methods. Thirty rabbits were divided into normal control group, model control group, and PPGS subgroups of 0.8, 1.6, and 3.2 mL/kg/day under random selection. In atherosclerosis model, the effects of PPGS on diverse blood lipids, foam cells number, and aortic morphology were evaluated. In the primary culture of endothelial cells (ECs), the activities of PPGS on both ECs proliferation and ECs injury were studied as well. Results. In atherosclerosis model, the hypolipidemic activities of PPGS were mainly focused on TC, LDL-C, and Lp(a). All changes on these factors were statistically significant compared with model group (P < 0.01), except TG and HDL-C. The intimal foam cell number of PPGS subgroups (0.8, 1.6, and 3.2 mL/kg/day) was significantly reduced than model control (P < 0.01). In the primary culture of endothelial cells (ECs), PPGS showed no effect on cell proliferation but preferred to protect EC from injury and apoptosis induced by H2O2 and lipopolysaccharide (LPS). Discussion and Conclusion. The antiatherosclerotic effect of PPGS may be supported by its hypolipidemic activities, improving aortic morphology, and reducing foam cells number and ECs injury.