Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy. Compression of the peripheral median nerve within the carpal tunnel at the wrist leads to a range of structural and functional changes, which ultimately leads to neuroplastic change in the central nervous system (CNS). CTS is characterized by dysesthesias, or unpleasant atypical sensations, and persistent pain. This symptomatology and peripheral nerve block change the quantity and quality of the somatosensory afference reaching the cortex, likely engendering central neuroplasticity. In fact, CTS provides an excellent opportunity to investigate cortical reorganization induced by clinically relevant aberrant afference in humans. Recent neuroimaging studies have applied techniques such as functional MRI (fMRI) and magnetoencephalography (MEG) to evaluate neuroplasticity in primary somatosensory cortex (SI) and elsewhere in the brain. This review will outline both peripheral pathophysiology characterizing chronic nerve compression, and the downstream central neuroplasticity that occurs with CTS and related nerve compression disorders. We will also detail therapeutic interventions that have demonstrated benefit for CTS. While surgery remains the definitive treatment for severe CTS, mild and moderate CTS may be treated with more conservative therapies, such as neuromodulation-based techniques, including TENS and electro-acupuncture. This review will also detail future directions for exploring neuroplasticity in CTS, as well as how better characterization of neuroplastic change in the CNS can inform the development of future therapeutic interventions.