Background DCAF7/WDR68 (hereafter WDR68) is a highly conserved WD40 repeat protein across species and its role in mouse embryonic development is still unknown. Methods The mice deficient in WDR68 function by gene targeting were generated for its functional research. Several single-cell RNA-sequencing datasets that collectively span mouse gastrulation and organogenesis were integrated for reconstruction of expression trajectory of WDR68 spanning mouse embryogenesis. Weighted gene co-expression network analysis (WGCNA) was used for functional enrichment of co-expression genes of WDR68 in early embryos. Whole-embryo transcriptomic analyses were employed to reveal differentially expressed genes in WDR68-knockout mouse embryos. Co-immunoprecipitation in combination with liquid chromatography-mass spectrometry analysis was performed to examine the interacting proteins of WDR68. Results WDR68 null mutants exhibited intrauterine growth retardation (IUGR) and died during gestation. Mechanistically, WDR68 deficiency resulted in deregulated expression of development-related genes and activated Hypoxia-inducible factor-1 (HIF-1) pathway. The interactomics confirmed that WDR68 interacts with development-related proteins including AUTS2 and PCGF5. Conclusions WDR68 is required for mouse embryonic development and may be a potential target for prevention and treatment of intrauterine growth retardation in the future.