De Bruijn was appointed Minister for Foreign Trade and Development Cooperation in the demissionary cabinet in August 2021, replacing Sigrid Kaag.

When Kaag resigned as Minister of Foreign Affairs the following month, De Bruijn took over the post in an acting capacity until the appointment of Ben Knapen.

[5] In his years at the Ministry of Foreign Affairs, he worked behind the scenes on the United Nations Convention on the Law of the Sea (1982) and the Treaty of Amsterdam (1997).

[6][7] De Bruijn was appointed Dutch permanent representative to the European Union in January 2003, succeeding Ben Bot, who had become the Minister of Foreign Affairs.

D66 had received a plurality of votes in the election, and De Bruijn was appointed nearly four weeks after scout Han Polman had published his report about possible coalitions.

[17] Due to legal issues, he initially wanted to discontinue the municipality's policy of lowering subsidies for organizations with managers earning more than a government minister.

The Council of State found the policy to be illegal in 2016, a month after De Bruijn had decided that 25 organizations would receive lower subsidies.

[18][19] De Bruijn subsequently advocated unsuccessfully for the laws to be changed such that local governments could restrict subsidies based on management income.

[20] As alderman, he was also responsible for the construction of several bicycle parking garages in the city center, and he assisted ADO Den Haag, which experienced financial hardship starting in 2015.

[34] It was announced on 14 July 2021 that De Bruijn would join the demissionary third Rutte cabinet as Minister for Foreign Trade and Development Cooperation, replacing D66's political leader Sigrid Kaag.

[35][36] Kaag announced her resignation as Minister of Foreign Affairs on 16 September after the House of Representatives had adopted a censure motion because of her handling of evacuations from Afghanistan following the fall of Kabul.

[38] He attended the 2021 United Nations Climate Change Conference (COP26) in Glasgow, where he signed an agreement to halt government financing for foreign fossil fuel projects.

[39] De Bruijn also started drafting legislation to oblige companies to adhere to corporate social responsibility principles in December 2021 after a similar proposal by the European Commission had been postponed.