Endometrial receptivity is a critical, time-limited state required for embryo implantation. In unexplained infertility, diagnosed when standard tests reveal no ovulatory, tubal, male, or uterine cause, implantation failure occurs despite apparently normal endometrial assessment suggesting hidden molecular dysregulation. Here integrated spatially resolved multi-omics, combining spatial transcriptomics and spatial proteomics is applied to mid-secretory endometrium from fertile women and women with unexplained infertility, using fertile proliferative endometrium as a non-receptive reference. We identify a reproducible, spatially distinct endometrial molecular state in unexplained infertility and reveal MORF4L2 as a candidate regulator of epithelial–embryo interaction, whose suppression significantly reduces embryo surrogate adhesion in vitro, functionally linking epithelial molecular alterations to impaired implantation. Across epithelial, stromal and endothelial compartments, this state is characterized by compartment-specific molecular alterations. At the luminal region, disrupted epithelial–stromal organization, dysregulated transcription factor networks, stromal inflammatory activation and enhanced endothelial–immune–epithelial signaling are detected. In deeper glandular region, epithelial secretory differentiation and stromal decidualization are impaired, as validated by spatial proteomics. These findings define unexplained infertility as a spatially reprogrammed endometrial state, reveal mechanisms by which disrupted regional regulation drives implantation failure, and demonstrate the potential of spatial multi-omics to uncover diagnostic and therapeutic targets in reproductive medicine.