Despite the regard in which he was held by the Venetians, Dürer was back in Nuremberg by mid-1507. He remained in Germany until 1520. His reputation spread all over Europe. He was on terms of friendship or friendly communication with all the masters of the age, and Raphael held himself honored in exchanging drawings with Dürer.

The years between his return from Venice and his journey to the Netherlands are commonly divided according to the type of work with which he was principally occupied. The first five years, 1507–1511, are pre-eminently the painting years of his life. In them, working with a vast number of preliminary drawings and studies, he produced what have been accounted his four best works in painting: Adam and Eve (1507), Virgin with the Iris (1508), the altarpiece the Assumption of the Virgin (1509), and the Adoration of the Trinity by all the Saints (1511). During this period he also completed the two woodcut series of the Great Passion and the Life of the Virgin, both published in 1511 together with a second edition of the Apocalypse series.  

From 1511 to 1514, Dürer concentrated on engraving, both on wood and copper, but especially the latter. The major work he produced in this period was the thirty-seven subjects of the Little Passion on wood, published first in 1511, and a set of fifteen small copper-engravings on the same theme in 1512. In 1513 and 1514 appeared the three most famous of Dürer's works in copper-engraving, The Knight, Death, and the Devil (or simply The Knight, as he called it, 1513), Melancholia I and St. Jerome in his Study (both 1514).  

In 'Melancholia I' appears a 4th-order magic square which is believed to be the first seen in European art. The two numbers in the middle of the bottom row give the date of the engraving: 1514. 

In the years leading to 1520 he produced a wide range of works, including tempera on linen portraits in 1516, engravings on many subjects, experiments in etching on plates of iron and zinc, and a part of the Triumphal Gate and the Triumphal March for the Emperor Maximilian. He also did the marginal decorations for the Emperor's prayer-book and a portrait-drawing of the Emperor shortly before his death in 1519.   

In the summer of 1520 the desire of Dürer to secure new patronage following the death of Maximilian and an outbreak of sickness in Nuremberg, gave occasion to his fourth and last journey. Together with his wife and her maid he set out in July for the Netherlands in order to be present at the coronation of the new Emperor Charles V. He journeyed by the Rhine to Cologne, and then to Antwerp, where he was well received and produced numerous drawings in silverpoint, chalk or charcoal. Besides going to Aachen for the coronation, he made excursions to Cologne, Nijmwegen, 's-Hertogenbosch, Brussels, Bruges, Ghent and Zeeland. He finally returned home in July 1521, having caught an undetermined illness which afflicted him for the rest of his life.

Back in Nuremberg, Dürer began work on a series of religious pictures. Many preliminary sketches and studies survive, but no paintings on the grand scale were ever carried out. This was due in part to his declining health, but more because of the time he gave to the preparation of his theoretical works on geometry and perspective, proportion and fortification. Though having little natural gift for writing, he worked hard to produce his works.  

The consequence of this shift in emphasis was that in the last years of his life Dürer produced, as an artist, comparatively little. In painting there was a portrait of Hieronymus Holtzschuher, a Madonna and Child (1526) and two panels showing St. John with St. Peter in front and St. Paul with St. Mark in the background. In copper-engraving Dürer produced only a number of portraits, those of the cardinal-elector of Mainz (The Great Cardinal), Frederick the Wise, elector of Saxony, and his friends the humanist scholar Willibald Pirckheimer, Philipp Melanchthon and Erasmus of Rotterdam.  

Of his books, Dürer succeeded in getting two finished and produced during his lifetime. One on geometry and perspective (The Painter's Manual), which was published at Nuremberg in 1525, and one on fortification, published in 1527. His work on human proportion was brought out shortly after his death in 1528 at the age of 56.