[7] Moratinos served as Minister of Foreign Affairs in the Government of José Luis Rodríguez Zapatero from 18 April 2004 until 21 October 2010, when he was replaced by Trinidad Jiménez.

By the end of 2009, Moratinos was mentioned by news media as a potential candidate for the position of High Representative of the Union for Foreign Affairs and Security Policy; the post later went to Catherine Ashton instead.

In 2010, he took part in the tripartite negotiations with Cuban President Raúl Castro and Roman Catholic bishop Jaime Ortega that resulted in pardons being granted to 52 Black Spring prisoners on the condition that they go into exile in Spain.

[19] In 2010, Moratinos was given a new mission as a special envoy trying to defuse a row between Israel and Egypt that threatened to derail, for the second time, a summit of the Union for the Mediterranean.

[26] From 2012 to 2013, Moratinos was a member of the High-Level Advisory Council of the President of the 67th Session of the United Nations General Assembly, Serbia's then foreign minister Vuk Jeremić.

[27] Following consultations, United Nations Secretary-General António Guterres appointed Moratinos as his High Representative for the Alliance of Civilizations in 2018, succeeding Nassir Abdulaziz Al-Nasser.