Cardinal Francisco Jiménez de Cisneros, a former student of the Estudio General de Alcalá, founded the Complutense University (also known as the University of Alcalá or Cisneriana) in 1499 thanks to three bulls granted by Pope Alexander VI. The name "Complutense" comes from Complutum, the Roman name for Alcalá de Henares, although its exact etymology is debated.

These bulls allowed Cisneros to legally establish the university, endow it with resources and confer official validity to its degrees. However, long before receiving papal approval, Cisneros had already begun the purchase of land and the construction of an innovative university complex, conceived as a "City of God" (Civitas Dei), considered the first university campus planned from scratch in history.

The first stone was laid in 1501, and classes began in 1508. By the academic year 1509-1510, five faculties were in operation: Arts and Philosophy, Theology, Canon Law, Letters and Medicine. Cisneros granted the institution Constitutions that regulated university life and outlined the rights and duties of its members.

Cisneros' project had three fundamental objectives: to train clerics with a reformed spirit and deep spiritual sense (religious), to prepare highly qualified professionals for administration and government (political), and to renew theological teaching under the ideals of classical humanism (cultural).

The university had two highest authorities: the rector, elected from the Colegio Mayor de San Ildefonso, and the chancellor, a position for life in the hands of the abbot of the Magisterial Church, with authority to grant academic degrees. Both positions were the protagonists of frequent tensions over the centuries.

The curriculum, centered on theology, also included philosophy, law, medicine, grammar, rhetoric and biblical languages. The Faculty of Theology taught three key currents of 15th century European thought -escoticism, nominalism and Thomism-, which made the university a model of Christian humanist education of great doctrinal breadth and international prestige.