John Knox is believed to have been born in Giffordgate, on the opposite bank of the of the River Tyne from St Mary's around 1514. He trained as a priest in St Mary's but never held a parish. Instead, he became a notary and then a tutor to landowning families near Haddington. These lairds supported the Reformer, George Wishart and Knox became a guide to Wishart as he travelled in the Lothians.
In January 1547, Wishart preached at two services in St Mary's with Knox standing guard, below the pulpit bearing a two handed sword. He was prepared to defend him against Cardinal Beaton's armed men but Wishart sent him away, saying "One's enough for the burning". Wishart was captured and burned at the stake at St Andrews. Knox was exiled for his non-conforming beliefs but was able to return to Scotland in 1558.
The Siege of Haddington in 1548 left St Mary's roofless for 14 years. The Catholic Church was not in a position to restore it as support for reformation grew. As the town council, with limited resources was considering what it could do, Knox is reputed to have suggested a barrier wall to restrict the church to the area of the nave, leaving the crossing and choir open to the sky. It may have suited Knox to shut from view of the congregation the high altar and its associations with popery. Things remained that way until the full restoration of 1972/73.
There is no record of Knox having preached in St Mary's, but, as he was ordained priest there and the inventory of his estate showed that he had a pension from the Kirk in Haddington, it seems likely.