The area is strewn with symbols and tools associated with craft and carpentry, including an hourglass, weighing scales, a hand plane, a claw hammer, and a saw.

The art historian Erwin Panofsky, whose writing on the print has received the most attention, detailed its possible relation to Renaissance humanists' conception of melancholia.

Summarizing its art-historical legacy, he wrote that "the influence of Dürer's Melencolia I—the first representation in which the concept of melancholy was transplanted from the plane of scientific and pseudo-scientific folklore to the level of art—extended all over the European continent and lasted for more than three centuries.

As the art historian Campbell Dodgson wrote in 1926, "The literature on Melancholia is more extensive than that on any other engraving by Dürer: that statement would probably remain true if the last two words were omitted.

[7][8] The prints are considered thematically related by some art historians, depicting labours that are intellectual (Melencolia I), moral (Knight), or spiritual (St. Jerome) in nature.

In 1513 and 1514, Dürer experienced the death of a number of friends, followed by his mother (whose portrait he drew in this period), engendering a grief that may be expressed in this engraving.

[9] Her face is relatively dark, indicating the accumulation of black bile, and she wears a wreath of watery plants (water parsley and watercress[20][21] or lovage).

Numerous unused tools and mathematical instruments are scattered around, including a hammer and nails, a saw, a plane, pincers, a straightedge, a molder's form, and either the nozzle of a bellows or an enema syringe (clyster).

[32] In contrast with Saint Jerome in His Study, which has a strong sense of linear perspective and an obvious source of light, Melencolia I is disorderly and lacks a "visual center".

[33] It has few perspective lines leading to the vanishing point (below the bat-like creature at the horizon), which divides the diameter of the rainbow in the golden ratio.

Addressing its apparent symbolism, he said, "to show that such [afflicted] minds commonly grasp everything and how they are frequently carried away into absurdities, [Dürer] reared up in front of her a ladder into the clouds, while the ascent by means of rungs is ... impeded by a square block of stone.

[36] Most art historians view the print as an allegory, assuming that a unified theme can be found in the image if its constituent symbols are "unlocked" and brought into conceptual order.

Merback notes that ambiguities remain even after the interpretation of numerous individual symbols: the viewer does not know if it is daytime or twilight, where the figures are located, or the source of illumination.

Melancholia was traditionally the least desirable of the four temperaments, making for a constitution that was, according to Panofsky, "awkward, miserly, spiteful, greedy, malicious, cowardly, faithless, irreverent and drowsy".

A few years earlier, the Viennese art historian Karl Giehlow had published two articles that laid the groundwork for Panofsky's extensive study of the print.

Giehlow found the print an "erudite summa of these interests, a comprehensive portrayal of the melancholic temperament, its positive and negative values held in perfect balance, its potential for 'genius' suspended between divine inspiration and dark madness".

In the engraving, symbols of geometry, measurement, and trades are numerous: the compass, the scale, the hammer and nails, the plane and saw, the sphere and the unusual polyhedron.

The figure wears a wreath of "wet" plants to counteract the dryness of melancholy, and she has the dark face and dishevelled appearance associated with the melancholic.

As art historian Philip Sohm summarizes, Ficino and Agrippa gave Renaissance intellectuals a "Neoplatonic conception of melancholy as divine inspiration ...

[47] The first, melancholia imaginativa, affected artists, whose imaginative faculty was considered stronger than their reason (compared with, e.g., scientists) or intuitive mind (e.g., theologians).

[48] Melencolia I portrays a state of lost inspiration: the figure is "surrounded by the instruments of creative work, but sadly brooding with a feeling that she is achieving nothing.

[58] In the 1980s, scholars began to focus on the inherent contradictions of the print, finding a mismatch between "intention and result" in the interpretive effort it seemingly required.

Joseph Leo Koerner abandoned allegorical readings in his 1993 commentary, describing the engraving as purposely obscure, such that the viewer reflects on their own interpretive labour.

Instead of mediating a meaning, Melencolia seems designed to generate multiple and contradictory readings, to clue its viewers to an endless exegetical labor until, exhausted in the end, they discover their own portrait in Dürer's sleepless, inactive personification of melancholy.

Dürer was exposed to a variety of literature that may have influenced the engraving by his friend and collaborator, the humanist Willibald Pirckheimer, who also translated from Greek.

He writes, the "thematic of a virtue-building inner reflection, understood as an ethical-therapeutic imperative for the new type of pious intellectual envisioned by humanism, certainly underlies the conception of Melencolia".

[63] The ambiguity of Melencolia I in this view "offers a moderate mental workout that calms rather than excites the passions, a stimulation of the soul's higher powers, an evacuative that dispels the vapors beclouding the mind...

[64] Artists from the sixteenth century used Melencolia I as a source, either in single images personifying melancholia or in the older type in which all four temperaments appear.

[65][66] They share elements with Melencolia I such as a winged, seated woman, a sleeping or sitting dog, a sphere, and varying numbers of children playing, likely based on Durer's Putto.

[68] The Renaissance historian Frances Yates believed George Chapman's 1594 poem The Shadow of Night to be influenced by Dürer's print, and Robert Burton described it in his The Anatomy of Melancholy (1621).