Little is known about Witz's life or training, but in 1434 he entered the painters' guild in Basel, where he worked most of his life. The Heilsspiegel altarpiece (c. 1435; now dispersed), generally agreed to be his earliest surviving work, displays numerous monumental, sculpturelike figures in small, bare rooms. In this altarpiece, such figures as the personification of “The Synagogue” are placed diagonally to the picture-plane in a simple, graceful pose, revealing Witz's youthful ability to manipulate space, despite the panel's inaccurate perspective.

Three panels from about 1440–43 are probably from a dispersed altarpiece. The “SS. Catherine and Mary Magdalene,” the “Meeting of Joachim and Anna,” and the “Annunciation” display a highly original handling of linear perspective, a sculptural sense of form, and a great sensitivity to the play of light upon the various textures of cloth, stone, and wood. The significance of these scenes is conveyed not through the use of the mystic symbolism prevalent in the art of northern Europe but through the faithful rendering of natural phenomena, making the scenes immediate and convincing. That aspect of Witz's art is best exemplified by his masterpiece, “The Miraculous Draft of Fishes” (1444). In this work, Witz's realism is so precise that he carefully distinguishes between the light reflected off the water's surface and the light reflected off the stones beneath the shallow water. He convincingly renders the reflections of the disciples, the boat, and the buildings on the shore, as well as accurately recording in the background the landscape around Geneva.