Timmermans began his career with the Dutch Ministry of Foreign Affairs in 1987. He has worked at the European Integration Department of the Dutch Ministry of Foreign Affairs and at the Embassy of the Netherlands in Moscow. He later worked for Hans van den Broek, European Commissioner for External Relations, and Max van der Stoel, High Commissioner on National Minorities for the OSCE.

In 1998, he was elected as a member of the House of Representatives for the Dutch Labour Party. In the fourth Balkenende government, from 2007 to 2010, he was Minister for European Affairs. In 2010, he returned to Parliament as the Labour Party's spokesperson.

In 2012, he became Minister of Foreign Affairs in the second Rutte government. In 2014, he became First Vice-President of the European Commission.

Since 2019, he is the Executive Vice-President of the European Commission, responsible for the Green Deal.