Lewes Priory was founded by William de Warenne and his wife Gundrada between 1078 and 1082 on the site of a Saxon church dedicated, like the Priory, to St. Pancras. William was a leading Norman baron with extensive lands in Sussex and elsewhere in England. Lewes was the first Priory in England belonging to the reformed Benedictine Order of Cluny, based in France. It became one of the wealthiest monasteries in England. However, in spite of its wealth it played little role in national affairs, except at the time of the Battle of Lewes in 1264 when it was occupied by the troops of King Henry III.

The main buildings, including the great Priory church, were put up in Quarr limestone in the Romanesque style between c1082 to c1100 and in Caen limestone from c1145 to the 13th century. Repairs and additions continued up to the monastery's dissolution in November 1537. At this time it owned over 20,000 acres in Sussex with other lands elsewhere, was the patron of 19 parish churches in the county and owned two houses for the poor in Lewes. There were only 24 monks at the time of its dissolution, compared with as many as 100 in the 12th and 13th centuries.

After the Dissolution and the demolition of the buildings the site was briefly owned by Thomas Cromwell, who had organised the dissolution of the monasteries in England. He built a substantial house on the site of the prior's lodgings, know as Lords Place, which was subsequently owned by the Sackville family. The house, the largest in Lewes, survived until after its sale in 1668 when it was gradually demolished. Dominating the site was the great 432 feet church, larger than Chichester Cathedral. In 1845 two lead caskets enclosing the bones of the founder and his wife were found while excavating the new railway between Lewes and Brighton which destroyed much of what remained of the great church, the cloister and the chapter house. They are preserved with Gundrada's Tournai marble tomb slab in Southover Church. This church was the priory's guest house before it became the parish church in the middle ages.