Potentilla anserina L. (PA) belongs to the Rosaceae family, is a common edible plant in the Qinghai-Tibet Plateau areas of China. This study elucidates the mechanism upon which crude polysaccharide of PA (PAP) on fat accumulation in HepG2 cells stimulated by oleic acid (OA) and high fat high sugar induced mice. The result revealed that PAP inhibited lipid accumulation in obese mice and ameliorated the degree of damage in OA-induced HepG2 cells. Specifically, compared to the control group, the TG and TC levels were decreased in cells and mice serum, the AST and ALT contents were declined in liver of obese mice by PAP treatment. The expressions of adipogenic genes of SREBP-1c, C/EBPα, PPARγ, and FAS were inhibited after PAP treatment. Moreover, PAP increased the mRNA levels of CPT-1 and PPARα, which were involved in fatty acid oxidation. The present results indicated the PAPcould alleviate the damage of liver associated with obesity and PAP treatment might provide a dietary therapeutic option for the treatment of hyperlipidemia.