Large-scale radiation catastrophes and localized exposure incidents remain major threats to public health. Effective treatment following radiation exposure is challenging because radiation dose, timing, and affected tissues can vary widely between individuals. To better understand the biological response to radiation injury, we employed a multi-omics approach integrating transcriptomics, proteomics, and metabolomics. In this study, mouse bone marrow was analyzed at 1, 6, and 24 h after whole-body irradiation and compared with bone marrow from non-irradiated mice. Multivariate and univariate analyses revealed time-dependent changes across transcriptomic, proteomic, and metabolomic profiles. We further applied machine learning-based integrative analysis and biomarker discovery approaches to identify key molecular responses associated with radiation exposure. Integrated analysis showed that the acute radiation response in bone marrow included immune-related processes, followed by intermediate metabolic reprogramming, and later disruptions in cell cycle regulation. Biomarker analysis identified several promising candidates, including the transcripts Sapcd2 and Cd28, proteins FRIL1 and CDK1, and the metabolites 3-hydroxyisobutyrate and taurine. Overall, our findings demonstrate that bone marrow from irradiated mice undergoes dynamic and coordinated molecular changes over time. These responses include activation of ferroptosis defense mechanisms, mitotic dysfunction, and pathways associated with programmed cell death.