Dia terlahir di desa Proti, Macedonia, Kesultanan Utsmaniyah (sekarang Yunani). Dia menjadi warganegara Yunani pada 1913, setelah Macedonia bersatu dengan Yunani isetelah Perang Balkan Kedua. Ayahnya bernama Georgios Karamanlis, seorang guru yang berperang ketika Greek Struggle for Macedonia, pada 1904–1908. Setelah menghabiskan masa kecilnya di Macedonia, dia pergi ke Athena untuk attain his degree in Law. He practised law in Serres, entered politics with the conservative People's Party and was elected Member of Parliament for the first time at the age of 28, in the Greek legislative election, 1936. Due to health problems, Karamanlis did not participate in the Greco-Italian War.