In time, all professors and students at the University of Heidelberg were forced to sign the Formula of Concord, which repudiated the Reformed confession.

As an alternative university for those who refused to sign, and therefore were forced to leave Heidelberg, Count Palatine Johann Casimir – who unlike his older brother Ludwig was an adherent of the Reformed Church – created the Casimirianum.

The institution was erected in 1578/79 through the rebuilding and expansion of the "white cell," a building with Gothic and Renaissance features, which was part of the former Augustinian cloister.

The university was equipped with Partikularschule and a Paedagogium (also called the “Gymnasium illustre”) upstream to enable students to prepare for advanced studies.

The university only remained in Neustadt for a few years; the faculty returned to Heidelberg in 1583/84 during Johann Casimir’s regency under Elector Frederick IV.