Abstract Cellular prion (PRNP) is a GPI anchored extrinsic membrane glycoprotein, which has been implicated in mouse decidualization. However, the molecular function of this protein, in mouse decidua is not known. In this report, we have characterized and elucidated the possible role of PRNP in mouse decidua. We demonstrated that PRNP expression is evident on embryonic day (E) 6.5 to E9.5 across the primary decidual zone (PDZ) in mouse implantation site. As gestation progressed, PRNP continued to be expressed in the receding decidua, up to E17.5. shRNA-mediated knock down of PRNP on E5.5 through E7.5 led to decreased expression of tight junction proteins (TJPs) in PDZ, in vivo. These included CINGULIN, AFADIN, CATENIN-α1, Lethal (2) giant larvae protein homolog 1, Caludin-5, and ICAM-1. Furthermore, PRNP-positive decidual cells, showed augmented expression of autophagic machinery. PRNP knockdown curtailed expression of autophagy-related genes in decidua in vivo. Our results highlight hitherto unknown novel functions of PRNP: a) an inducer of TJPs at PDZ, which protects the developing embryo, b) a decision maker protein between life and death in decidual cells.