Peripheral nerve injuries (PNIs) represent a significant clinical challenge, especially with aging when axonal remyelination and regeneration are compromised. This study explores the therapeutic potential of inhibiting glutamate carboxypeptidase II (GCPII), a neuropeptidase involved in glutamate signaling, for promoting remyelination following PNI. GCPII activity was significantly upregulated following PNI, but was normalized with the selective GCPII inhibitor 2-(phosphonomethyl)-pentanedioic acid (2-PMPA) treatment (7464 ± 626 vs. 10,047 ± 440 vs. 1504 ± 89 fmol/mg/h; p < 0.05, n = 3). Immunostaining confirmed that the elevation of GCPII was predominantly in activated macrophages and repair Schwann cells. In vitro, 2-PMPA treatment enhanced myelination in dorsal root ganglion (DRG) explants, with a significant increase in myelin segments (17.67 ± 3.48 vs. 72.67 ± 4.37; p < 0.05, n = 3). In vivo, using a sciatic nerve crush injury model in aged mice, 2-PMPA significantly accelerated remyelination, as evidenced by a decreased g-ratio (0.90 ± 0.01 vs. 0.73 ± 0.05; p < 0.05, n = 3) and a higher percentage of remyelinated axons (28.1 ± 2.1 vs. 82.5 ± 7.2%; p < 0.05, n = 3). Further, we targeted GCPII inhibition specifically on macrophages and Schwann cells using dendrimer-conjugated 2-PMPA. Electrophysiological assessments of nerve conduction speed via compound muscle action potential (CMAP) recordings demonstrated a significant decrease in CMAP latency after 10 weeks of GCPII inhibition in aged PNI mice (4.04 ± 0.11 vs. 3.23 ± 0.13 ms; p < 0.01, n = 5). These findings suggest that GCPII inhibition is a promising therapeutic strategy to enhance remyelination following PNI, particularly in elderly patients where this process is compromised.