On 9 January 1919, Kafantaris joined the Cabinet of Greece under Prime Minister of Greece Eleftherios Venizelos as Minister of Agriculture. He went on to disagree with him as far as holding the 1920 Greek legislative election while the Hellenic Army was still involved in the Greco-Turkish War. Venizelos accepted his resignation on 4 February 1920.
He only returned following the defeat of Greece in the Greco-Turkish War and was named Minister of Justice. On 19 February 1924, Prime Minister Eleftherios Venizelos resigned due to health reasons and nominated Kafantaris as his successor. Kafantaris served as Prime Minister for almost a month and then resigned himself on 12 March 1924 after a failed assassination attempt. He was succeeded by Alexandros Papanastasiou.
He died in Athens in 1946, and is buried in the First Cemetery of Athens.