The effect of spinal cord stimulation (SCS) using differential target multiplexed programming (DTMP) on proteins involved in the regulation of ion transport in spinal cord (SC) tissue of an animal model of neuropathic pain was evaluated in comparison to low rate (LR) SCS. Rats subjected to the spared nerve injury model (SNI) and implanted with a SCS lead were assigned to DTMP or LR and stimulated for 48 h. A No-SCS group received no stimulation, and a Sham group received no SNI or stimulation. Proteins in the dorsal ipsilateral quadrant of the stimulated SC were identified and quantified using mass spectrometry. Proteins significantly modulated by DTMP or LR relative to No-SCS were identified. Bioinformatic tools were used to identify proteins related to ion transport regulation. DTMP modulated a larger number of proteins than LR. More than 40 proteins significantly involved in the regulation of chloride (Cl), potassium (K), sodium (Na), or calcium (Ca) ions were identified. SNI affected proteins that promote the increase of intracellular Ca, Na, and K and decrease of intracellular Cl. DTMP modulated proteins involved in glial response to neural injury that affect Ca signaling. DTMP decreased levels of proteins related to Ca transport that may result in the reduction of intracellular Ca. Presynaptic proteins involved in GABA vesicle formation and release were upregulated by DTMP. DTMP also upregulated postsynaptic proteins involved with elevated intracellular Cl, while modulating proteins, expressed by astrocytes, that regulate postsynaptic Cl inhibition. DTMP downregulated K regulatory proteins affected by SNI that affect neuronal depolarization, and upregulated proteins that are associated with a decrease of intracellular neuronal K and astrocyte uptake of extracellular K. DTMP treatment modulated the expression of proteins with the potential to facilitate a reversal of dysregulation of ion transport and signaling associated with a model of neuropathic pain.