Background <p>Acute neuroinflammation drives secondary degeneration after spinal cord injury (SCI), yet the precise immune cell states and upstream regulatory circuits that initiate this response remain unresolved. Defining these early-state determinants at multi-omics resolution is essential for identifying mechanistically grounded therapeutic targets.</p> Methods <p>We implemented an integrated multi-omics framework combining high-temporal-resolution single-cell RNA sequencing, bulk transcriptomics, histological validation, and systems-level network modeling across uninjured and early post-injury time points. Cell-cell communication analysis delineated intercellular signaling architecture within the acute lesion niche. Transcriptional regulatory network inference with in silico perturbation identified candidate master regulators. Network-based compound prioritization and target engagement validation were followed by functional testing in activated macrophages and a mouse SCI model.</p> Results <p>We resolved a temporally restricted S100a4⁺ macrophage state that rapidly emerged after injury, peaked at 1&#xa0;day, and subsequently contracted. This state was defined by a coordinated transcriptional program integrating enhanced migratory capacity, amplified pro-inflammatory and pyroptotic signaling, and repression of homeostatic and reparative modules, constituting the dominant acute inflammatory signature at the tissue level. Systems-level analysis established a <i>Cebpb</i>-centered regulatory circuitry governing this state, thereby defining a C/EBPβ-S100a4⁺ macrophage axis as a principal driver of early neuroinflammation. Network topology positioned this axis as a densely connected and self-reinforcing hub within the injury microenvironment. Computational drug prioritization identified baicalein as a candidate regulator of C/EBPβ-dependent signaling. ChIP-qPCR and nuclear-cytoplasmic fractionation validated that baicalein effectively reduced the nuclear translocation of C/EBPβ and its binding to the S100a4 promoter. Experimental validation demonstrated that baicalein suppressed C/EBPβ expression, attenuated downstream inflammatory and pyroptotic pathways, and significantly improved functional recovery following SCI.</p> Conclusion <p>This study delineates a C/EBPβ-S100a4⁺ macrophage axis that mechanistically structures the acute inflammatory landscape of SCI and represents a tractable therapeutic vulnerability. These findings advance a state-specific, network-informed framework for early immunomodulation in spinal cord injury.</p>