His pre-eminence derives from eclecticism and the spirit of humanity that permeate his art. Even during his apprenticeship, Berruguete had to struggle to master a number of divergent influences. After an early period in Flanders, or in the profoundly Flemish atmosphere of the Castilian Gothic, he went to Italy, where he remained for several years. These different elements of his training, perfectly assimilated by his unusually receptive, but stoutly Spanish nature, led him to a style rooted in Gothic ideals and Gothic forms, but Renaissance in the warmth of its humanism. His later painting reveals a certain progression toward a Hispano-Flemish Gothicism.
The first historical reference to Berruguete relate to his stay at Urbino. The great condottiere, Federigo di Montefeltro, duke of Urbino, had summoned Joos van Wassenhove to decorate the library and study of his magnificent palace with allegories of the liberal arts and portraits of Biblical and pagan thinkers. Berruguete may have collaborated with him, but there is no doubt that the allegories and many of the more vigorous portraits of the series are by his hand alone. He also painted the solemmn portrait of Federigo and his son (Ducal Palace, Urbino), which gives some idea of his mastery of tactile values and of the airy qualities of physical space, perfectly suggested in depth. These paintings were all executed between 1480 and 1481. During his stay at Urbino, Berruguete completed a certain amount of work which has since remained in Italy. Moreover, he also painted the hands of the portrait of Montefeltro in the famous picture by Piero della Francesca in the Brera Gallery, Milan.
In 1483 Berruguete was busy in Toledo cathedral, working on the now-lost mural decoration of the cloister. Judging from its style the retable of Santa Eulalia in his native village must have been painted during the last ten years of the fifteenth century. Its narrative scenes, the naturalism of which reflects the life of contemporary Castile, gave the artist an opportunity to demonstrate his ability and the final victory over primitivism. The figures of kings and prophets on the predella establish Berruguete as the forerunner of the Spanish portraitists of the seventeenth century. His retable of St John the Baptist, preserved in Santa Maria del Campo (Burgos), is impressive in the strength of the figures and the clarity of the construction. Even more important, as an ensemble, is the retable of St Thomas in Avila, the best of its numerous scenes being the vision of the saint overcoming temptation. The persistence of the Gothic tradition is revealed in the free use of gold and the abundance of brocades.
Among Berruguete's numerous works hardly less important than the previously cited are the Annunciation in the Carthusian monastery of Miraflores and the Holy Family signed and dated 1500, now in a private collection in Paredes de Nava.
Berruguete's influence is strongly apparent in the work of various painters who were active in Castile and Leon during the first third of the sixteenth century.