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Assisted reproductive technology has been widely applied in the treatment of human infertility. However, accumulating evidence indicates that in vitro fertilization (IVF) is associated with a low pregnancy rate, placental defects, and metabolic diseases in offspring. Here, we find that IVF manipulation notably disrupts extraembryonic tissue-specific gene expression, and 334 epiblast (Epi)-specific genes and 24 Epi-specific transcription factors are abnormally expressed in extraembryonic ectoderm (ExE) of IVF embryos at embryonic day 7.5. Combined histone modification analysis reveals that aberrant H3K4me3 modification at the Epi active promoters results in increased expression of these genes in ExE. Importantly, we demonstrate that knockdown of the H3K4me3-recruited regulator Kmt2e , which is highly expressed in IVF embryos, greatly improves the development of IVF embryos and reduces abnormal gene expression in ExE. Our study therefore identifies that abnormal H3K4me3 modification in extraembryonic tissue is a major cause of implantation failure and abnormal placental development of IVF embryos. [Display omitted] • IVF affects implantation, extraembryonic ectoderm (ExE), and placental development • IVF disrupts extraembryonic tissue-specific gene expression in ExE • Aberrant H3K4me3 in ExE causes gene expression and developmental defects • Kmt2e knockdown improves the development of IVF embryos Bai et al. show that IVF manipulation disrupts extraembryonic ectoderm (ExE) gene expression and placental development. Aberrant histone H3K4me3 in ExE is an important cause for embryo implantation failure and extraembryonic developmental abnormalities. Kmt2e knockdown improves the development of IVF embryos and reduces abnormal gene expression in ExE. [ABSTRACT FROM AUTHOR]