The aim of this study was to develop an advanced in vitro model of human endometrium using single-cell-derived endometrial epithelial organoids, enabling the study of embryo secretome-endometrial crosstalk at the maternal-fetal interface. Single-cell-derived organoids generated from endometrial tissue of a parous 39-year-old woman recapitulated hormone-responsive decidualization, as demonstrated by expression of SPP1 and acetyl-α-tubulin. When cultured in embryo culture media, organoid viability was maintained with no cytotoxicity, but proliferation was suppressed, likely due to the lower concentrations of the required factors in organoid growth media. Organoids were stimulated with culture supernatants from morphologically good-quality embryos with known pregnancy outcomes (live birth (n = 4) vs no pregnancy (n = 4)). Transcriptomic profiling (RNA-sequencing) revealed that 32 genes were differentially expressed (DEGs) in organoids exposed to the culture supernatants from live-birth embryos versus non-pregnant outcomes: 24 upregulated and 8 downregulated. These DEGs were enriched for biological processes related to cell motility and cytoskeletal dynamics. In conclusion, soluble factors secreted by human blastocysts achieving live birth selectively modulate the endometrial epithelial transcriptome, enhancing pathways involved in cytoskeletal remodeling and immune modulation. This embryo-directed remodeling likely facilitates endometrial receptivity for successful implantation to occur. Our organoid model provides a robust platform for further investigating implantation failure.