During World War I, Spaak lied about his age to be accepted in the Army; he subsequently spent two years as a German prisoner of war.
In 1935 he entered the cabinet of Paul Van Zeeland as Minister of Transport. In February 1936 he became Minister of Foreign Affairs, serving first under Zeeland and then under his uncle, Paul-Émile Janson. From May 1938 to February 1939 he was Prime Minister for the first time.
He was Foreign Minister again from September 1939 until August 1949 under the subsequent Prime Ministers Hubert Pierlot, Achille Van Acker and Camille Huysmans. During this time he twice was appointed Prime Minister as well, first from 13 to 31 March 1946 - the shortest government in Belgian history, and again from March 1947 to August 1949.
Spaak was an advocate of Belgium's "independence policy" before World War II. During the German invasion in May 1940, he fled to France and tried to return during the summer but was prevented by the Germans, even he was Foreign Minister as the time. Hence, against his wishes he settleed in Britain.
Spaak became a staunch supporter of regional co-operation and collective security after 1944. While still in exile in London, he promoted the creation of a customs union uniting Belgium, The Netherlands and Luxembourg (see Benelux). In August 1946, he was elected chairman of the first session of the consultative Assembly of the Council of Europe. From 1952 to 1953, he presided the General Assembly of the European Coal and Steel Community.
In 1955, the Messina Conference of European leaders appointed him as chairman of a preparatory committee (Spaak Committee) charged with the preparation of a report on the creation of a common European market. The so-called "…Spaak Report" formed the cornerstone of the Intergovernmental Conference on the Common Market and Euratom at Val Duchesse in 1956 and led to the signature, on 25 March 1957, of the Treaties of Rome establishing a European Economic Community and the European Atomic Energy Community (Euratom). Paul-Henri Spaak signed the treaty for Belgium, together with Jean Charles Snoy et d'Oppuers. His role in the creation of the EEC earned Spaak a place among the Founding fathers of the European Union.
In 1956, he was chosen by the Council of the North Atlantic Treaty Organisation to succeed Lord Ismay as Secretary General. He held this office from 1957 until 1961, when he was succeeded by Dirk Stikker. Spaak was also instrumental in the choice of Brussels as the new seat of the Alliance's HQ in 1966.
This was also the year of his last European campaign, when he played an important conciliatory role in resolving the "empty chair crisis" by helping to bring France back into the European fold. In 1957 he received the Karlspreis (engl.: Charlemagne Award) an Award by the German city of Aachen to people who contributed to the European idea and European peace.
He and his wife Marguerite Malevez had two daughters—Antoinette Spaak led the Democratic Front of Francophones—and a son, the diplomat Fernand Spaak. After her death in August 1964, he married Simone Dear in April 1965. His niece was the actress Catherine Spaak. During the 1940s, during his time in New York with the United Nations, he also had an affair with the American fashion designer Pauline Fairfax Potter (1908-1976).