Genscher was born at Reideburg (Province of Saxony), now a part of Halle, in what later became East Germany. He was drafted to serve as a member of the Air Force Support Personnel (Luftwaffenhelfer) at the age of 16. In 1945 he became a member of the Nazi Party. According to Genscher's statements, this happened through a collective application in his Wehrmacht unit and against his own intentions.

Genscher fought as a young man in the Wehrmacht at the end of the Second World War. In 1945, Genscher was a young soldier in General Walther Wenck's 12th Army. Genscher briefly became an American and British prisoner of war. After World War II, he studied law and economics at the universities of Halle and Leipzig (1946 – 1949) and joined the East German Liberal Democratic Party (LDPD) in 1946.

In 1952, Genscher fled to West Germany, where he joined the Free Democratic Party (FDP). He passed his second state examination in law in Hamburg in 1954 and became a solicitor in Bremen.

In 1965 Genscher was elected on the North Rhine - Westphalian FDP list to the West German parliament and remained a member of parliament until his retirement in 1998. After serving in several party offices, he was appointed Minister of the Interior by Chancellor Willy Brandt, whose Social Democratic Party was in coalition with the FDP, in 1969; in 1974, he became foreign minister and Vice Chancellor.

In 1972, while Minister of the Interior, he rejected Israel’s offer to send an Israeli special forces unit to Germany to deal with the Black September hijacking of the 1972 Summer Olympics. The crisis ended in a bloody shootout at Fürstenfeldbruck Air Base which left 11 hostages, 5 terrorists, and 1 German policeman dead. Genscher's popularity with Israel declined further when he endorsed the handing over of the three captured hijackers to the Palestinians following the hijacking of a Lufthansa plane on 29 October 1972.

In the SPD - FDP coalition, he helped shape Brandt's policy of deescalation with the communist East, commonly known as Ostpolitik, which was continued under Helmut Schmidt after Brandt's resignation in 1974.

Still, Genscher was one of the FDP's driving forces when, in 1982, the party switched sides from its coalition with the SPD to support the CDU / CSU in their Constructive Vote of No Confidence to have Helmut Schmidt replaced with Helmut Kohl as Chancellor. Despite the great controversy that accompanied this switch, he remained one of the most popular politicians in West Germany. He retained his posts as foreign minister and vice chancellor through German reunification and until 1992, when he stepped down for health reasons.

He is mostly respected for his efforts that helped spell the end of the Cold War, and which led to German reunification, when Communist eastern European governments toppled in the late 1980s; for example, he visited Poland to meet Lech Wałęsa as early as 1988. In 1988, he was awarded the Prize For Freedom of the Liberal International. One event remembered by many is his 30 September 1989 speech from the balcony of the German embassy in Prague, in whose courtyard thousands of East German citizens had assembled to flee to the West, when he announced that he had reached an agreement with the Communist Czechoslovakian government that the refugees could leave: "We have come to you to tell you that today, your departure ..." (German: "Wir sind zu Ihnen gekommen, um Ihnen mitzuteilen, dass heute Ihre Ausreise ..."). After these words, the speech drowned in cheers.

In 1991, Genscher raced to recognize the Republic of Croatia in the Croatian War of Independence shortly after the Serbian attack on Vukovar. The rest of the European Union was pressured to follow suit soon afterward.

Genscher was also an active participant in the further development of the European Union, taking active part in the Single European Act Treaty negotiations in the mid 1980s, as well as the joint publication of the Genscher - Colombo plan with Italian Minister of Foreign Affairs Emilio Colombo which advocated further integration and deepening of relations in the European Union towards a more federalist European State.

Having finished his political career, Genscher has been active as a lawyer and in international relations organizations. He founded his own Hans - Dietrich Genscher Consult GmbH in 2000.