Various building works were still in progress when the religious and political upheaval of the 1530s brought the life of the Priory to an abrupt end. In 1535 Richard Layton, one of Thomas Cromwell's royal commissioners, visited the Priory. He reported 'serious failings' including corruption and 'treasonable offences'. Whether these allegations were true or not it is impossible to say. In 1536 Parliament passed a law dissolving the smaller monasteries in England and Wales. Fearing the worst, in November 1537 Lewes's prior, Robert Crowham, and the monks "voluntarily" signed the surrender of the Priory to the government. While elsewhere in the country abbots were executed for opposing the dissolution, Robert Crowham was able to secure valuable offices including appointment as treasurer of Chichester cathedral. The fate of most of the 24 monks is known. They were granted pensions or accepted appointments as priests in Sussex. The dissolution of the major monasteries was confirmed by the act of 1539.
Early in 1538 the Priory passed into the hands of Thomas Cromwell and the destruction of the religious buildings began. The Italian engineer Giovanni Portinari arrived from London with a gang of seventeen men to carry out this work. They did this by undermining the walls and setting fires. The physical evidence to support Portinari's description of exactly how this massive feat was achieved so quickly can best be seen in the remains of the first church. Here the angle of the surviving walls shows how they were brought down. Lead from the roof was melted down on site in purpose-built portable furnaces, while the Caen and Quarr stone and flint were loaded onto carts, or barges at the quayside, and removed for re-use elsewhere in Lewes and its vicinity. Many of the stones were re-used in house in Lewes and can still be seen, most notably at Southover Grange. The site reverberated as the huge towers and walls crashed to the ground. The precinct must have resembled a vast reclamation yard, as the contraclors sorted through the material and set about its disposal. Surprisingly there is no record of any disturbances or protests by the local population against the destruction of the Priory. The Priory was looted and graves were smashed and robbed. Relics or shrines that had not already been destroyed, or secretly stashed away were now considered valuable pickings for the demolition squad.