Legend states that Matsys abandoned his career as a blacksmith to woo his wife, who found painting to be a more romantic profession, though Karel van Mander claimed this to be false, and the real reason was a sickness during which he was too weak to work at the smithy and instead decorated prints for the carnival celebrations.

It is widely believed that Joachim Patinir studied with Matsys at some point during his career and contributed to several of his landscapes (such as The Temptation of St. Anthony at the Prado Museum in Madrid).

[5] Because no guild records were kept prior to 1494 in Leuven there is no concrete proof that Matsys attained his master's status there; however, historians generally accept this to be the location of his early training because he had not been previously registered in Antwerp as an apprentice.

[6] Although the roots of Matsys' training are unknown, his style reflects the artistic qualities of Dirk Bouts, who brought to Leuven the influence of Hans Memling and Rogier Van der Weyden.

His most well known satirical works include A Portrait of an Elderly Man (1513), and The Money Changer and His Wife (1514), all of which provide commentary on human feeling and society in general.

[5] Most of the emphasis in his works lies not upon atmosphere, which is in fact given very little attention, but to the literalness of caricature: emphasizing the melancholy refinement of saints, the brutal gestures and grimaces of gaolers and executioners.

His Virgin and Christ, Ecce Homo and Mater Dolorosa (London and Antwerp) are known for their serene and dignified mastery, gaining in delicacy and nuance in the works of his maturity.

His sister Catherine and her husband suffered at Leuven in 1543 for what was then the capital offence of reading the Bible: he being decapitated, she allegedly buried alive in the square before the church.

Benefactor Cornelius van der Geest is said to be responsible for the wording, stating: "in his time a smith and afterwards a famous painter", keeping in accordance with the legends surrounding Matsys' humble beginnings.

It is likely a depiction of a real person with Paget's disease,[9] though it is sometimes said to be a metaphorical portrait of the Margaret, Countess of Tyrol, who was known as Maultasch, which, though literally translated "satchel mouth", was used to mean "ugly woman" or "whore" (because of her marital scandals).

Commissioned for the Church of Saint Peter in Leuven, they reflect strong religious feeling and precise detailing characteristic to the majority of his works.

The earliest of his works, a St Jerome dated 1537, in the gallery of Vienna, as well as the latest, a Healing of Tobias of 1564, in the museum of Antwerp, are evidence of his tendency to substitute imitation for originality.

Matsys was a cult figure during the 17th century in Antwerp [clarification needed] in addition to being one of the founders of the local school of painting (which climaxed with the career of Peter Paul Rubens).