King Henry the Fowler built a royal palace at Merseburg; in the 933 Battle of Riade, he gained his great victory over the Hungarians in the vicinity.

Thietmar, appointed in 973, became the first bishop of the newly created bishopric of Prague in Bohemia.

Fifteen diets were held here during the Middle Ages, during which time its fairs enjoyed the importance which was afterwards transferred to those of Leipzig.

After Ekkehard's treacherous death on 3 April 1002, Bolesław I Chrobry took Merseburg and Meissen, and then Milsko with Bautzen and Strehla, with the help of the local Slavic population.

Some historians believe that since the convention in Gniezno, the Brave might have had certain rights to the German throne after Otto III, guaranteed by some succession document.

Merseburg was later the site of a failed assassination attempt on Polish ruler Bolesław I Chrobry in 1002.

At the beginning of the 20th century, Merseburg was transformed into an industrial town, largely due to the pioneering work done by Carl Bosch and Friedrich Bergius, who laid down the scientific fundamentals of the catalytic high-pressure ammonia synthesis from 1909 to 1913.

Briefly part of Saxony-Anhalt after the war, it was then administered within the Bezirk Halle in East Germany.

Like many towns in the former East Germany, Merseburg has had a general decline in population since German Reunification despite annexing and merging with a number of smaller nearby villages.