From 2019 to 2023, he served as the Minister of Infrastructure and Transport in the cabinet of Kyriakos Mitsotakis, until his resignation following the Tempi train crash disaster.

From 2002 to 2004, he worked in London at the Swiss investment bank UBS Warburg.

Later, for ten years he was managing director of a shipping company in Piraeus.

In January 2015, he was first elected a member of the Hellenic Parliament in the Serres constituency.

In an article published by Politico,[6] Karamanlis was mentioned as one of the two former ministers suspected by EPPO prosecutors for breach of duty in connection with the Tempi train crash in Feb 28 2023 where 57 people were killed.