He went to Nuremberg for his education when he was thirteen years of age, and soon afterwards to the university of Erfurt, where he took his bachelor's degree in 1499. There he attracted the notice of Nikolaus Marschalk, the most influential professor, who made Spalatin his amanuensis and took him to the new university of Wittenberg in 1502. In 1505 Spalatin returned to Erfurt to study jurisprudence, was recommended to Conrad Mutianus, and was welcomed by the little band of German humanists of whom Mutianus was chief.
He got a post as teacher in the monastery at Georgenthal, and in 1508 he was ordained priest by Bishop Johann von Laasphe, who had ordained Luther. In 1509 Mutianus recommended him to Frederick III. the Wise, the elector of Saxony, who employed him to act as tutor to his nephew, the future elector, John Frederick. Spalatin speedily gained the confidence of the elector, who sent him to Wittenberg in 1511 to act as tutor to his nephews, and procured for him a canon's stall in Altenburg. In 1512 the elector made him his librarian. He was promoted to be court chaplain and secretary, and took charge of all the elector's private and public correspondence. His solid scholarship, and especially his unusual mastery of Greek, made him indispensable to the Saxon court.
Spalatin had never cared for theology, and, although a priest and a preacher, had been a mere humanist. How he first became acquainted with Luther it is impossible to say - probably at Wittenberg; but the reformer from the first exercised a great power over him, and became his chief counsellor in all moral and religious matters. His letters to Luther have been lost, but Luther's answers remain, and are extremely interesting. There is scarcely any fact in the opening history of the Reformation which is not connected in some way with Spalatin's name. He read Luther's writings to the elector, and translated for his benefit those in Latin into German. He accompanied Frederick to the Diet of Augsburg in 1518, and shared in the negotiations with the papal legates, Cardinal Cajetan and Karl von Miltitz. He was with the elector when Charles was chosen emperor and when he was crowned. He was with his master at the Diet of Worms. In short, he stood beside Frederick as his confidential adviser in all the troubled diplomacy of the earlier years of the Reformation. Spalatin would have dissuaded Luther again and again from publishing books or engaging in overt acts against the Papacy, but when the thing was done none was so ready to translate the book or to justify the act.
On the death of Frederick the Wise in 1525 Spalatin no longer lived at the Saxon court. But he attended the imperial diets, and was the constant and valued adviser of the electors, John and John Frederick. He went into residence as canon at Altenburg, and incited the chapter to institute reforms somewhat unsuccessfully. He married in the same year. During the later portion of his life, from 1526 onwards, he was chiefly engaged in the visitation of churches and schools in electoral Saxony, reporting on the confiscation and application of ecclesiastical revenues, and he was asked to undertake the same work for Albertine Saxony. He was also permanent visitor of Wittenberg University. Shortly before his death he fell into a state of profound melancholy, and died on the 16th of January 1545, at Altenburg.
He married in 1525.