Abstract Aims The aim of this study was to investigate the anti-proliferative effect of Lycium barbarum polysaccharide (LBP) on MCF-7cells. Main methods MCF-7 cells were treated with 0, 10, 30, 100, and 300μg/ml LBP for 24h. The cell cycle distribution was analyzed by flow cytometry. MEK inhibitor, U1206 also was added in MCF-7 cells to deal with LBP (300μg/ml) for different times (0, 2, 4, 6, 8, 16, 24h). Western blotting was used to indicate changes in the levels of ERK (extracellular signal‐regulated protein kinase) and phosphorylation-ERK (p-ERK) to compare the relationship between ERK activity and LBP. The expressions of p53, p-p53 and p21 were observed by western blotting to analyze the relationship between p53 and ERK which was under the treatment of LBP. Key findings The MCF-7 cell cycle was arrested in S phase with the treatment of LBP. The LBP can also activate ERK, which may be associated with p53 pathway. There was a dose-dependent increase in the relation between the degree of ERK activation and LBP. Significance LBP induces the anti-proliferation of MCF-7 cells by activating ERK.