After an obscure early period Wolgemut married (1472) Barbara, widow of the Nürnberg painter Hans Pleydenwurff. In the next 40 years he produced a series of large altarpieces, rich with carving and gilding, as well as portraits and book illustrations. The altarpiece of St. Jacob, Straubing, is attributed to the beginning of this activity (c. 1475–76), and those of the Marienkirche, Zwickau (1476–79), the Stiftskirche, Feuchtwangen (1484), the Heiligkreuzkirche, Nürnberg (1486), and the Stadtkirche of Schwabach (1506–08) are all known to be products of his workshop. With his stepson Wilhelm Pleydenwurff, Wolgemut completed the designs for the 650 woodcuts of Hartmann Schedel's Liber chronicarum in 1493 and the woodcuts for Stephan Fridolin's Schatzbehalter der wahren Reichtümer des Heils (1491).

No powerful artistic personality emerges from these works. As a painter, Wolgemut was a competent technician, adapting 15th-century early Netherlandish styles to local taste. His designs for woodcut extended the range of that medium but were rapidly surpassed by his most famous pupil, Albrecht Dürer.