Experimental autoimmune encephalomyelitis (EAE) is a key model of autoimmune neuroinflammation, yet an integrated characterization of transcriptional dysregulation in the central nervous system has been limited. In this study, we performed proteomic profiling of dysregulated gene expression in the spinal cord of female and male C57BL/6JRccHsd mice induced with EAE during the acute disease phase using TMT LC-MS/MS. The associated transcriptomics dataset (RNA-sequencing analysis of transcriptomic changes in the spinal cord during experimental autoimmune encephalomyelitis) can be found on GEO. We identified extensive upregulation of innate and adaptive immune response signatures alongside downregulation of neuronal, synaptic, and mitochondrial pathways at the transcript level. Comparative analyses revealed broad pathway‑level changes associated with neuroinflammation, while highlighting limitations of transcriptomics alone in capturing alterations related to synaptic and metabolic integrity. This dataset provides a resource for investigating molecular remodeling of the inflamed central nervous system during autoimmune neuroinflammation.