In 1992 he became official spokesman of the Greek Ministry of Foreign Affairs and was appointed Consul General of Greece in Geneva.

In March 2001, he split from New Democracy with his Movement of Free Citizens (KEP), but in a surprising move merged back in June 2002.

On 11 November 2011 he was appointed Minister for National Defence in the coalition government of Lucas Papademos, resigning from his parliamentary seat, thus adhering to the New Democracy policy that no serving Opposition Party Deputies may hold ministerial office.

After the Cabinet reshuffle of 25 June 2013 he became Greek Minister for Defence again, serving until his nomination as Greece's European Commissioner in November 2014.

On 27 July 2014, Prime Minister Antonis Samaras nominated Avramopoulos as Greece's next member of the European Commission.

[4] Samaras also defied calls from the centre-left Pasok party for Maria Damanaki to continue as European Commissioner.

From the outset of his political career, Avramopoulos served for twenty years as Honorary President of the Athens’ International Prize for Democracy for UNESCO in Paris (until 2013).

He has also been Chairman of the Steering Committee on Cities´ Diplomacy, established by the Global Forum (Rome) and the World Bank Institute (Washington D.C.).

Avramopoulos has a friendly relation with the Turkish President Recep Tayyip Erdoğan since they were Mayors of Athens and Istanbul respectively.

In November 2017, he became Honorary Member of the Propeller Club of the United States Port of Piraeus and he received the Award of Excellence of the Propeller Club of the United States Port of Piraeus for his strenuous effort and impact on developing a new European Policy on regular Migration.

In December 2017, the Department of International and European Studies of the University of Piraeus awarded Mr. Avramopoulos the first "Themistocles" prize for his contribution to the management of the EU migration and security crisis.