Genthin Castle was first mentioned in an 1144 deed, it was the residence of the Plotho noble family who then served as ministeriales of the Archbishops of Magdeburg. The surrounding settlement was documented as a town in 1459, its citizens were vested with market rights in 1539.
The town's economy was decisively promoted by the building of the Elbe–Havel Canal from 1743 onwards and the opening of the Berlin–Magdeburg railway line in 1846. A detergent factory was opened in 1921 by Henkel.
On the night of 21–22 December 1939, at least 186 (according to other sources: 278) people were killed in a train crash at Genthin station, making it one of the deadliest railway accidents in Germany. A monument to the victims was erected in the town. In 1943 a subcamp of Ravensbrück concentration camp was built in Genthin for about 1,000 female prisoners and forced labourers. After World War II, Genthin was part of the Soviet occupation zone.