He was finance minister of Luxembourg from 1979 until 1989, and Prime Minister of Luxembourg from 1984 to 1995, as a member of the Christian Social People's Party, which has been the leading party in the Luxembourg government since 1979. As Prime Minister of Luxembourg he also led the negotiations on the Single European Act, which effectively set aside the 20-year old Luxembourg Compromise.

Santer became the ninth President of the European Commission in 1995 as a compromise choice between the United Kingdom and a Franco-German alliance, after the Franco-German nominee Jean-Luc Dehaene was vetoed by British prime minister John Major. Santer selection was barely ratified by a European Parliament upset with the process for which Commission presidents are selected.

In the same year, 1995, Santer became the first recipient of the Vision for Europe Award.

Allegations of corruption concerning individual EU-commissioners led to an investigation into administrative failings (incompetence and malpractice) by an independent group of experts. Despite clearing most commissioners, the report stated that they had not found a single person showing the slightest sense of responsibility. Because the implicated commissioners refused to resign and because the President of the European Commission did not have the power to dismiss individual commissioners, Santer and his entire commission resigned on March 15, 1999, the very day of the report's publication (see Santer Commission: Resignation).

From 1999 until 2004, Santer was a member of the European Parliament. He also was on General Mediterranean Holdings' board, a financial holding owned by Anglo-Iraqi Nadhmi Auchi.

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ECSC: Jean Monnet (1952) • René Mayer (1955) • Paul Finet (1958) • Piero Malvestiti (1959) • Rinaldo Del Bo (1963) • Albert Coppé (1963)EAEC: Louis Armand (1958) • Étienne Hirsch (1959) • Pierre Chatenet (1962)

EEC: Walter Hallstein (1958)2 EC: Jean Rey (1967) • Franco Maria Malfatti (1970) • Sicco Mansholt (1972) •François-Xavier Ortoli (1973) • Roy Jenkins (1977) • Gaston Thorn (1981) • Jacques Delors (1985)2EU: Jacques Delors (1993) • Jacques Santer (1995) • Manuel Marín (1999) • Romano Prodi (1999) • José Manuel Barroso (2004)2