Objective To explore the regulation of astragalus polysaccharide (APS) on esophageal cancer cells.Methods Different concentrations of APS were taken to figure out their effects on tumor formation and on the cell proliferation and apoptosis in nude mice in vivo and in vitro. In vivo, we first made an injection of esophageal cancer cells to the nude mice, then the tumor growth trends and its suppression rates were detected after the other injection of APS in different concentrations. In vitro, the cell cycle and apoptosis rates of esophageal cancer cells were detected through EdU staining and flow cytometry after the treatment of different concentrations of APS. The qPCR, Western blotting and Co-IP assay were used to investigate the molecular mechanism of APS regulation on esophageal cancer.Results The tumor proliferation was inhibited after APS treatment and the effect of tumor suppression was enhanced with the dose raising. APS can reduce the proliferation of esophageal cancer cell and promote its apoptosis. The expression of TP73 and FBXW7 was increased along with the raising concentrations of APS, while the expression of Ki67 and BCL-2 was decreased. The Co-IP results revealed that APS was able to bind to the protein of TP73. Overexpressed TP73 could suppress the cell proliferation and promote the apoptosis of esophageal cancer cells, while silenced TP73 did the opposite.Conclusion This study revealed the regulatory effects of APS on esophageal cancer and its possible molecular mechanism, which provided a certain research basis for the treatment of esophageal cancer and the application of APS.