Structural maintenance of chromosome flexible domain containing 1 (Smchd1) is a chromatin regulatory gene for which mutations are associated with facioscapulohumeral muscular dystrophy and arhinia. The contribution of oocyte- and zygote-expressed SMCHD1 to early development was examined in mice ( Mus musculus) using a small interfering RNA knockdown approach. Smchd1 knockdown compromised long-term embryo viability, with reduced embryo nuclear volumes at the morula stage, reduced blastocyst cell number, formation and hatching, and reduced viability to term. RNA sequencing analysis of Smchd1 knockdown morulae revealed aberrant increases in expression of a small number of trophectoderm (TE)-related genes and reduced expression of cell proliferation genes, including S-phase kinase-associated protein 2 ( Skp2). Smchd1 expression was elevated in embryos deficient for Caudal-type homeobox transcription factor 2 ( Cdx2, a key regulator of TE specification), indicating that Smchd1 is normally repressed by CDX2. These results indicate that Smchd1 plays an important role in the preimplantation embryo, regulating early gene expression and contributing to long-term embryo viability. These results extend the known functions of SMCHD1 to the preimplantation period and highlight important function for maternally expressed Smchd1 messenger RNA and protein.