The monastery was founded in 1089 at the time of the Investiture Controversy by Counts Gero and Kuno of Achalm, advised by Bishop Adalbero of Würzburg and Abbot William of Hirsau.

Benedictine Ernest Weinrauch was a highly respected organ player and contrapuntist, who composed an oratorio at Zwiefalten.

On 25 November 1802, however, it was secularised and dissolved and became a lunatic asylum and later psychiatric hospital, which it is today, as well as the site of the Württemberg Psychiatry Museum.

The present buildings were constructed in German Baroque style from 1739–47 under the direction of Johann Michael Fischer (1692–1766) of Munich, who began overseeing the work in 1741.

The interior, considered a model of Baroque design, is filled with ornate chapels and gilded balustrades, dominated by the high altar, which combines a Gothic statue of the Virgin Mary dating from 1430 with Baroque additions (dating from about 1750) by Johann Joseph Christian (1706–77).