Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating, often dose-limiting, side effect of taxane-based chemotherapy, a cornerstone of breast cancer treatment. Despite its prevalence, no FDA-approved therapies exist for the prevention or treatment of CIPN, underscoring the need for mechanistic preclinical studies. Using label-free liquid chromatography coupled to electrospray ionization mass spectrometry (LC-ESI MS/MS), we investigated the effect of 4 doses of 8 mg/kg paclitaxel on the lumbar (L4-L6) spinal cord proteome of an MMTV-PyMT–derived breast cancer model in C57BL/6J mice. Results show that breast cancer alone was associated with a significant change in the expression of 630 proteins, while paclitaxel treatment of breast cancer tumor-bearing mice significantly altered 204 proteins. Furthermore, we identified 67 altered proteins that are shared between breast cancer and paclitaxel associated proteomes. An analysis of enrichment based on gene ontology (GO) and STRING protein-protein interaction (PPI) network showed that paclitaxel treatment within this breast cancer model modified mitochondrial metabolism, ion transport, and neurotransmitter signaling pathways. Functional enrichment underscores the interaction between breast cancer and paclitaxel-mediated proteome changes related to neuronal activation, including upregulation of specific amino acid transporters. Taken together, these findings reveal pathways of translational relevance to CIPN management during breast cancer chemotherapy.