About 1100, Jocelin of Sempringham replaced the Saxon church with a new church dedicated to St Andrew. Jocelin had a son named Gilbert, and it is St. Gilbert of Sempringham (canonized in 1202) whose name will forever be associated with the site.

In 1131, Gilbert built a simple range of buildings against the north wall of the church, with accommodation for seven local women, who vowed to live a life of charity, obedience, chastity, and humility. This was the beginning of the Gilbertine Order, the only completely British monastic order during the Middle Ages. The original monastic buildings proved inadequate, and in 1139, Gilbert received a grant of land from Gilbert de Gant (Ghent) to erect a new priory about 350 yards away to the south west.

Sempringham Priory was a double house, with provision for both men and women (though the genders were segregated) and grew to provide a home for 200 nuns and 40 canons. The canons served as priests, and observed a mix of Augustinian and Premonstratensian rules. The order was known for a strict interpretation of those rules, so strict in fact that in 1170, the lay brothers serving at Sempringham rebelled and appealed to the Pope to relax the harshness of priory life.

By the time Gilbert died in 1189, there were 13 Gilbertine priories scattered around England. This number eventually rose to 25 by the time of the Reformation. When Gilbert was canonized, in 1202, his body was exhumed from its place between the altars in the priory church, encased in a lead coffin, and reburied, but the site of the grave has been lost.

When Edward I defeated Prince Llewellyn of Wales in 1283, he captured the prince's 17 month old daughter and heir, Gwenllian. Edward could not bring himself to murder the child, but feared her presence as a focus for Welsh rebellion, so he asked the Prior of Sempringham to admit Gwenllian to the priory. In 1327, his grandson Edward III visited the priory and provided an annual stipend of 20 pounds to pay for her keep. The princess was not a nun, and not in holy orders, she was a prisoner, unable to leave the priory. Gwenllian lived out her days at Sempringham and died in 1337. A memorial made of Welsh slate to the 'last princess of Wales' stands on the path to the parish church of St Andrew, and is a frequent destination for Welsh pilgrims.

Sempringham Priory survived until 1538, when it was dissolved by Henry VIII. The estate was purchased by the Clinton family, the monastic buildings pulled down, and a large Tudor house erected, only to be pulled down about 1616, before completion, and its plinth banked up to form an earthwork. The only tangible reminders of the important priory and the Gilbertines are St. Gilbert's Well, the memorial to Gwenllian, and the fishponds of the Priory.