Synchronization of preimplantation embryo development to blastocysts is one of the prerequisites for normal embryo implantation. While previous studies have ascribed an adverse effect to aberrant opioid signaling on embryo and fetal development, it has remained unclear whether the opioid system is operative in early pregnancy events. In the present study, employing multiple pharmacological and genetic approaches, we demonstrated that preimplantation embryos spanning the zygote to blastocyst express the opioid receptor subtypes and the oviduct expresses endogenous opioid precursors dynamically, which suggest that opioid signaling is functionally operative during preimplantation embryo development. Subsequent analysis further revealed that an aberrantly activated opioid signaling by morphine can remarkably derail normal preimplantation embryo development via inhibiting intracellular calcium mobilization, while a cotreatment of naloxone with morphine can remarkably reverse the adverse effects of morphine on preimplantation embryo development. Besides shedding light on the pathophysiological significance of the opioid system during early embryo development in mice, our findings have potential clinical relevance because an abused use of illicit opiate drugs is frequently associated with retarded fetal development and pregnancy failure in women.