Embryonic ectoderm development (EED) has become a novel target for cancer treatment. In this study, a series of EED inhibitors was subjected to a three-dimensional quantitative structure-activity relationship (3D-QSAR) and molecular docking. Accordingly, this is the first of such 3D-QSAR studies in a series of EED inhibitors displaying anti-cancer pharmacological profiles. The CoMFA (q² = 0.792, r² = 0.994, r²_pred = 0.74) and CoMSIA (q² = 0.873, r² = 0.994, r²_pred = 0.81) models demonstrated good robustness and predictive ability. Moreover, molecular docking suggested that cation-p,p-p stacking and hydrogen bonding interactions were the main factors affecting the activity of these inhibitors. Five new small molecules were designed based on the CoMFA and CoMSIA contour maps. These molecules were then submitted to further ADME studies, in which the ADME properties of the five designed molecules were found to be within a reasonable range. In view of the corresponding findings, this study may provide theoretical guidance for the rational design of novel EED inhibitors.