He later served as head of cabinet for First Vice-President of the European Commission Frans Timmermans and his successor Wopke Hoekstra.

NRC newspaper editor Coen van Zwol called their campaign fresh, clear and sharp (Dutch: fris, helder en scherp).

He was nineteenth on the list of candidates in the 2006 Dutch general elections receiving a relative high number of 6248 preferential votes.

[9] In April 2008, Samsom was a candidate to succeed Jacques Tichelaar as parliament party leader, but eventually he lost the vote to Mariëtte Hamer.

Jacques Tichelaar became the leader of the parliamentary party shortly after the 2006 general election in February 2007[10] but fell ill in January 2008.

[14] All 33 PvdA parliamentarians gathered two days later to discuss the position and cast their votes, resulting in a victory for Hamer.

[15] According to pollster Maurice de Hond, a majority of the 2006 Labour voters preferred Samsom as party leader.

During the Dutch Presidency of the Council of the European Union in early 2016, Diederik Samsom is credited with masterminding a key provision in the deal between the EU and Turkey.

[24] In November 2019, Samsom became head of cabinet for Frans Timmermans, First Vice-President of the European Commission and Commissioner for Climate Action.

[25] He became chair of the supervisory board of state-owned natural gas infrastructure and transportation company Gasunie in July 2024, saying that he wanted to help execute the renewable energy transition.

He failed to inform the European Commission of his new position as is required to prevent conflicts of interest, but the body finally allowed the appointment of Samson under certain conditions.

Samsom mentioned them in several political debates and interviews in a for the Netherlands unprecedented and criticized way, including drawing attention to his daughter's disability.

[30] He also involved his private life and family in his 2012 electoral campaign, most notably by featuring his two children in an official party TV advertisement.

[31][32] Samsom lived on a houseboat in Broek in Waterland with his ex-wife (then girlfriend) and daughter before moving to Leiden, where he still resides as of 2012.