The exact, underlying cause of primary empty sella syndrome is unknown (idiopathic). Researchers believe that a defect in the diaphragma sellae that is present at birth (congenital defect) plays a role in the development of primary empty sella syndrome. The diaphragma sellae is a fold of dura mater (the outermost layer of the membranes that line the brain and spinal cord). The diaphragma sellae covers the sphenoid bone where the sella turcica and the pituitary are located. In some affected individuals a tear in the diaphragma sellae allows the underlying membranes to push through (herniate), which allows cerebrospinal fluid to leak out and accumulate in the sella turcica. The pressure exerted by the fluid can flatten or enlarge the sella turcica. Consequently, the pituitary becomes compressed and flattened as well. In some individuals with primary empty sella syndrome the diaphragma sellae is absent at birth. The exact role that defects in the diaphragma sella play is the development of primary empty sella syndrome is unknown. Whether it causes primary empty sella syndrome directly, occurs as part of a larger disease process or is only a predisposing factor to the development of the disorder is unresolved.

Secondary empty sella syndrome is caused by a variety of different conditions including injury or trauma to the head, treated pituitary tumors, infection, radiation therapy, surgery on the pituitary region, or rare disorders such as Sheehan syndrome.