On the 28th of January 1546, Luther set off from Wittenberg to Eisleben accompanied by his friends Philip Melancthon and Justus Jonas. The Duke of Mansfeld had requested his services as a mediator in a long-running dispute in the area and Luther was happy to oblige. He was greeted with the ceremony and pomp befitting a nobleman and escorted to his quarters by a guard-of-honor made up of a hundred horsemen.

The mediation dragged on from the 29th of January until the 17th of February. That evening, after the mediation ended Luther fell ill. At first, neither Melancthon nor Jonas were overly worried and convinced Luther to stay in bed and rest. He awoke at midnight gravely ill and Melanchthon and Jonas were summoned to his bedside. Among his last words was the prayer "I pray to God to preserve the doctrine of His gospel among us for the Pope and the Council of Trent have grievous things at hand"

He died a short time later at 3 am on the 18th of February 1546 at the age of sixty-three. His coffin was displayed in Eisleben for two days before it was moved to Wittenberg where it was finally laid to rest on the 22nd of February 1546 under the pulpit of the Castle Church.

Justus Jonas preached his funeral sermon in Eisleben while Johann Bugenhagen, his friend and pastor who had married him and Katharina more than twenty years before preached his final funerary oration in Wittenberg.

Before he died Luther ominously declared "after my passing, dangerous times will come" and sure enough the Holy Roman Empire spiraled into chaos and war in the aftermath of his death. But despite the opposition the Reformation faced, both in the form of armed warfare and more subtle spiritual warfare through the agency of the Council of Trent and the counter-Reformation, the work that God had begun through Martin Luther irrecovacably transformed the world.