There was a significant outbreak of plague in Edinburgh and Leith in April 1585. Sick people were isolated on the town's common grounds. Robert Rollock closed the town's college, the University of Edinburgh, from May 1585 to February 1586. The first known death was a woman living in Fishmarket Close.
There was plague in July 1584 at West Wemyss in Fife, said to have brought from Flanders. In September 1584 it was said that four servants had died at the court of King James VI. The King went to Perth, where Lupold von Wedel saw him in St John's Kirk, and then to Stirling Castle to avoid the plague. In March 1585, Margaret Fleming, Countess of Atholl, was staying in Edinburgh's Canongate. She wrote to Mary, Queen of Scots, that she had found it difficult to send a letter "by reason of the contagious sickness that hath been, and yet is in this realm". There was plague in Perth, and a collection for relief was organised by the lawyers Oliver Colt and David Lawtie. As many as 1427 people died in Perth between September 1584 and August 1585. James VI suspended the holding of any court cases in Edinburgh concerning people living north of the River Forth.
A woman's death from plague on 30 April 1585 in Simon Marjoribank's house in Fishmarket Close came to the attention of the Edinburgh burgh council. According to Robert Johnston's account, she was first thought to have been in labour. It was said she had brought the plague from Perth. The records of the burgh council say the death was in McCalyeon's lodging within John Young the tailor's land in Fishmarket Close, and the tailor and his colleague (a "marrow") had visited other houses in the town. The houses were to be enclosed or shut up and watched. On 5 May, watchers were appointed at the West Port and Nether Bow to prevent vagabonds who might be infected entering the city, especially those coming from the ferry over the Forth at South Queensferry.
By 9 May, two more people had died in John Young's land, and three who were still alive were to be taken outside the city limits at the house of the late Adam Purves beside St Roch's Chapel. Two plague cleansers, Alexander French and John Spier, were summoned from Dysart and Wemyss to look after the "seik folkis". The cleansers wore black jupes with a white patch or band so they could be recognised. The clothing of the sick was burnt. One of the children of the miller Walter Ochiltree died, and the rest of the family was sent to the lodgings being built near Adam Purvis's house. Alexander Smith was appointed as executioner of the "foul folk" for those found guilty of concealing infected people. A man was executed for stealing "foul gear" in June.
James Stewart, Earl of Arran was Provost of Edinburgh. He left the city and entertained James VI at Dirleton Castle for twelve days in May 1585, while there was plague in Edinburgh. The entertainment included a sumptuous banquet and a Robin Hood play. James VI returned to Edinburgh, visting St Giles Cathedral on 9 June, then went to Falkland Palace in Fife, where he received English and Danish ambassadors. According to David Calderwood, the plague followed in King James's wake.
James Henrysoun was appointed as surgeon to visit and diagnose the sick. A place was built to keep the possesions of the infected at the lower entrance of Greyfriars Kirkyard near Cowgatehead. Steven Bannatyne made inventories of goods in houses suspected to be infected and Francis Loch, a "fowleman", took charge of such "foul goods". Cleansing of houses in the town seems to have involved fumigation with smoke, and John Kerr's house caught fire.
A shelter called the "Greitt Fowle Luge" was built on the Burgh Muir at "Adam Purvis's Acres" for sick people. The site was near Canaan Lane in present day Morningside. The "cleansed" were lodged to the west of this building, and newly suspected "foul" persons to the east. John Forrest was Master of the Cleansers, and another cleanser was appointed Bailie of the Muir. Robert Fairlie of the Braid provided a house for a brewery. There were so many people on the muir that the council ordered that their beer should be brewed thinner. Cleansed persons allowed home were confined to their houses for 15 days. A light coffin or bier of sawn deals was made for burials of the infected dead.
In July 1585, Alexander Smith, the "fowle hangman", was chained to the gibbet for a time for disobedience. William Fairlie was asked to provide the "foul-clengers" on Edinburgh burgh moor, who disinfected plague victim's goods, with a staff topped with a wicker taper. The Danish ambassadors' proposals were planned to be heard at a Convention of the Three Estates at Cupar in July, and a Parliament was held at St Andrews at the end of the month. In August, the plague came to St Andrews and James VI went on a progress and hunting trip to Loch Lomond. Four Flemish cleansers were employed in Edinburgh in September. They were allowed the use of the late Mungo Brady's house.
Edward Wotton wrote that the plague was in most of the "good towns" of Scotland in September 1585 and that Edinburgh and St Andrews "through the great mortality are almost desolate". In October, James VI went further into the countryside to attend the wedding of Lord Fleming at Kincardine Castle at Auchterarder. James VI was unable to raise a force to resist his rebels lords, Mar, Angus, and the Master of Glamis, who came from exile in England to Stirling in November and ousted his favourite James Stewart, Earl of Arran.
In December 1585, James VI moved from Stirling and set up the courts and exchequer at Linlithgow Palace and held a Parliament. Almost at the end of the epidemic, Edinburgh burgh council transferred the sick to a property known as the "White House" owned by Euphame MacCalzean. James VI returned via Corstorphine to Edinburgh Castle then Holyrood Palace in the first week of January 1586.
Robert Birrell wrote than many people Edinburgh during the epidemic. He estimated that 14,000 people died. In October 1585, Patrick Whitelaw of Newgrange wrote that more than 9,000 had died in Edinburgh. Calderwood wrote that 20,000 died in Edinburgh.
A number of wills entered in registers held by National Records of Scotland record deaths from the "pest", or in the "tyme of pest".