Peripheral nerve injuries (PNIs) pose major therapeutic challenges, particularly in aging individuals where remyelination and axonal regeneration are compromised. Age-associated dysfunction of repair Schwann cells and macrophages contributes to this failure, and elevated glutamate can further decrease their function. Glutamate carboxypeptidase II (GCPII), a neuropeptidase that regulates glutamate signaling, is upregulated after injury and represents a promising therapeutic target for PNI. In a mouse PNI model, GCPII activity increased in the nerve and denervated muscle post injury, and this increase was inhibited by treatment with the selective GCPII inhibitor 2-PMPA (control=7464±626; PNI=10047±440; PNI+2PMPA=1504±89 fmol/mg/h; p<0.001). Immunostaining localized the elevated GCPII to activated macrophages and repair Schwann cells. Functionally, 2-PMPA treatment enhanced myelin formation in mouse dorsal root ganglion (DRG) explants (vehicle=17.7±3.5; 2PMPA=72.7±4.4 segments; p<0.05) and improved remyelination in aged mice as evidenced by lowering the g-ratio (PNI=0.90±0.01; PNI+2PMPA=0.73±0.05; p<0.05) and increasing the percent of remyelinated axons (PNI=28.1±2.1%; PNI+2PMPA=82.5±7.2%: p<0.01). Similar to our murine findings, human patients with PNI have higher GCPII activity in nerve (control=852.5±186.2; PNI=1533±10.5) and muscle (control=657.6±160.4; PNI=1272±201.6). The elevation trended to be higher in older PNI patients. To overcome the poor oral bioavailability of 2-PMPA, we developed tetra(ODOL)-2-PMPA, a lipophilic prodrug achieving ~80-fold higher bioavailability in mice and ~44-fold in dogs. Oral dosing of tetra(ODOL)-2-PMPA reduced elevated nerve GCPII activity in aged PNI mice by approximately 40% within 3h (20421±1,321 to 12266±399 fmol/mg/h; p<0.001). These findings establish GCPII as a clinically relevant target for promoting remyelination and report the first orally bioavailable GCPII inhibitor with translational potential to improve recovery after PNI, particularly in the aging population.