Actually, an ancient name of the river is not documented, it is mentioned as Oddera in the 991 Dagome iudex referring to the realm of Prince Mieszko I of Poland.

The Alma Mater Viadrina was founded on 26 April 1506 by Elector Joachim I Nestor, with permission from Pope Julius II, as the first principal university of the Margraviate of Brandenburg.

The Viadrina enjoyed an excellent reputation in Brandenburg and the surrounding regions, and its graduates had high positions in administration, politics, law and the church.

One of its earliest chancellors, Bishop Georg von Blumenthal (1490–1550) was a vigorous opponent of the Protestant Reformation and did his utmost to expel Lutherans such as Jodocus Willich.

After the ruling House of Hohenzollern had converted to Calvinism, the 'Great Elector' Frederick William and his governor Prince John Maurice of Nassau-Siegen in 1655 founded the University of Duisburg, a Reformed college in the Duchy of Cleves.

Frederick William also opened the Frankfurt University for Jewish students, against fierce resistance by the teaching staff.

In 1736 the eminent jurist Johann Jakob Moser was called to head the Faculty of Law at the university, but had to leave after three years due to his thoroughly Liberal ideas which were disliked by the Prussian king Frederick William I.

In the course of the Prussian Reforms during the Napoleonic Wars, the University of Frankfurt was moved to Breslau (present-day Wrocław, Poland) in 1811.

The two universities jointly operate the Collegium Polonicum, located just opposite Viadrina on the Polish side of the Oder River.