Ionizing radiation (IR) can severely damage bone marrow (BM) by inducing DNA damage, oxidative stress, apoptosis, and disruption of the hematopoietic microenvironment. However, the molecular mechanisms underlying early radiation-induced BM injury remain incompletely understood. This study aimed to identify key radiation-responsive pathways and hub genes using an integrative bioinformatics approach. Public RNA-seq data from mouse BM hematopoietic stem cells collected 3 days after whole-body irradiation were analyzed. Differentially expressed genes were identified using two statistical approaches, followed by Gene Ontology, KEGG, Gene Set Enrichment Analysis, and Network-based protein-protein interaction analysis. Irradiation-induced transcriptional changes were mainly associated with cytokine signaling, hematopoietic regulation, immune responses, and extracellular matrix remodeling. KEGG highlighted cytokine-cytokine receptor interaction, hematopoietic cell lineage, JAK-STAT, and PI3K-Akt signaling, while GSEA indicated inflammatory, stress-response, and metabolic alterations. Four consensus hub genes, Il6, Cd34, Gypa, and Pdgfrb, were identified. These findings suggest that radiation-induced BM injury involves coordinated inflammatory, hematopoietic, and microenvironmental changes, and these hub genes may serve as candidate molecular indicators of hematopoietic damage.