[N 3] One of Hieronymus's older brothers, François [N 4] (1455–1502), filled several political and ecclesiastical functions, including Archbishop of (the Imperial City of) Besançon, under Philip the Handsome, in the transition period from Burgundian to Habsburg Netherlands.

From around 1485, Hieronymus studied in Leuven (under the early humanist Leo Outers), then in Orléans, and finally in Padua where he met Cuthbert Tunstall, who would later write to Henry VIII about his friend.

In his diplomatic function, he visited Pope Julius II in Rome and in 1508 welcomed the Holy Roman Emperor, Maxilimilian of Austria, at Mechelen.

During Archduchess Margaret of Austria's regency[N 5] he led a life of patron and humanist in Mechelen at the Hof van Busleyden, which city palace he had built in a very early Renaissance style[N 6] At the time tutoring Margaret's nephew Charles, Adriaan Boeyens visited the house, well before he became pope.

Hieronymus van Busleyden held positions in the Catholic Church: archdeacon of Our Lady's in Cambrai (1503), provost of St. Peter's in Aire-sur-la-Lys and canon of St. Rumbold's in Mechelen, St. Lambert's in Liège, St. Waltrude's in Mons, and St. Gudula in Brussels.