The cause of trigeminal neuralgia is very complicated. However, it's believed that physical nerve damage and stress can trigger the beginning of the painful attacks. Nerve damage may occur as the nerve passes from the openings in the skull to the muscles and tissue of the face. As the damage compresses the nerve, the nerve cells shed a protective and conductive coating known as myelin.

Myelin acts as an insulator. Without this insulation, information from nerves would be transmitted inefficiently. This may result in weakness, sensory loss or other neurologic dysfunction. Damage may also be the result of a biochemical change in the nerve tissue itself or an abnormal blood vessel compressing the nerve as it exits from the brain. In almost all cases, an excessive burst of nervous activity from a damaged nerve causes the painful attacks.

In people without TN, blood vessels are usually not in contact with the trigeminal nerve root entry zone. Though pulsation of vessels upon the trigeminal nerve root do not visibly damage the nerve, the irritation from repeated pulsations may lead to changes of nerve function and delivery of abnormal signals to the trigeminal nerve nucleus. Over time, this may cause hyperactivity of the trigeminal nerve nucleus which results in the generation of TN pain.