Decidual macrophages constitute 20–30% of the total leukocytes in the pregnant uterus, which regulates maternal immune tolerance and placenta development. Abnormal number or activities of decidual macrophages are associated with fetal loss and pregnancy complications such as preeclampsia. Monocytes differentiate into decidual macrophages in a decidua-specific microenvironment. Despite their important roles in pregnancy, the factors regulating the differentiation of decidual macrophages remain unclear. Glycodelin-A (GdA) is a glycoprotein found abundantly in the decidua and plays an important role in fetomaternal defense and placental development. It modulates the differentiation and activities of several immune cell types residing in the decidua. In this study, we demonstrated that GdA induced differentiation of human monocytes towards decidual macrophage-like phenotypes in terms of transcriptome, cell surface markers expression, secretome, and regulated trophoblast and endothelial cell functions. Siglec-7 mediated the binding and biological actions of GdA in a sialic acid-dependent manner. In summary, GdA induces the polarization of monocytes towards decidual macrophages for regulating fetomaternal tolerance and placental development.