This dataset contains paired tissue and serum proteomic & metabolomic raw MS data from 59 endometrial cancer (EC) patients and 32 age-matched healthy controls. Tissue proteomics was detected by DIA LC-MS (Orbitrap Exploris 480); tissue & serum metabolomics were acquired by untargeted DDA LC-MS (Orbitrap Fusion Lumos). Serum DIA proteomics was also performed. We screened differential molecules, performed pathway enrichment, and constructed a multi-omics diagnostic model with biomarkers CFHR3, LAMP2, L-valine and L-isoleucine. All raw LC-MS files, QC data and matched clinical metadata are deposited here.