The exact cause of lymphocytic colitis is unclear. It can sometimes be related to autoimmune diseases or infection. Autoimmune conditions cause the immune system to attack healthy cells in the body, often causing inflammation, as is found in lymphocytic colitis. Some researchers believe it is caused by something unfamiliar in the digestive tract, such as bacteria, pollen, or foods previously foreign to the body.

Certain medicines are also known to occasionally cause the condition. These include antidepressants, anti-inflammatories found in certain pain medications excluding steroids, medications for high cholesterol, medications for acid reflux, and medications for diabetes. Smoking is also linked to the development of lymphocytic colitis, often occurring after the patient quits smoking. Other studies have found a connection between coffee drinking and lymphocytic colitis, but these findings are not well documented.