On his return to Greece, Protopapadakis taught until 1890 when he was assigned the task of building the Corinth Canal. Afterwards, he designed and completed several railroad lines, making a name for himself as a top Greek engineer.
In 1902 he entered politics. He came to serve as Minister of Finance in several governments and, between May 22 and September 10, (May 9 - August 27 OS) 1922, as Prime Minister. It was during this tenure that the front collapsed during the Greco-Turkish War (1919-1922), resulting in the Asia Minor Disaster. Protopapadakis was deemed responsible for the catastrophe and was put on trial along with his mentor, Dimitrios Gounaris and four others. The six men were executed in Goudi, Athens on the morning of November 28 (November 15 OS), 1922.