The see was founded in 967 by Emperor Otto I at the same time in the same manner as those of Meissen and Zeitz (from 1029: Naumburg), all suffragan dioceses of the Archbishopric of Magdeburg as part of a plan to bind the adjacent Slavic ("Wendish") lands in the Saxon Eastern March beyond the Saale River more closely to the Holy Roman Empire.

Confirmed by Pope John XIII at the 968 synod in Ravenna, the first Merseburg bishop was Boso, a Bavarian monk descending from St. Emmeram's Abbey in Regensburg (Ratisbon), already distinguished by his missionary labours among the pagan Sorbs.

Upon Archbishop Gisilher's death in 1004, King Henry II re-established the prince-bishopric; the diocese did not, however, recover all its former territory, and was now almost exclusively a missionary jurisdiction among the Sorbs, who were not fully converted to Christianity until the middle of the 12th century.

From the 13th century onwards, the bishops had to deal with rising power of the Meissen margraves of the Wettin dynasty, from 1423 Electors of Saxony, who by denying Merseburg's Imperial immediacy attempted to acquire the overlordship.

The bishopric's fate was sealed with the Protestant Reformation, which was enforced here during the episcopate of Prince Adolph II of Anhalt, who was driven out of office by his uprising subjects during the German Peasants' War in 1525.