Enrico De Nicola was born in Naples and became famous as one of the most esteemed penal lawyers in Italy. He was elected a deputy for the first time in 1909 and he filled minor governmental posts until the advent of fascism, when he retired from political life. He was appointed senator by King Victor Emmanuel III in 1926, but he never took part in the workings of the Assembly.

After 1943, when fascism ended, De Nicola was perhaps the most influential mediator for the creation of the title "Lieutenant-General of the Realm", by which the king's son Prince Umberto took over most of the functions of the sovereign. Once the monarchy had ended, the Constituent Assembly elected De Nicola Provisional Head of State on 28 June 1946, with 80% of the votes, at the first round of voting. Giulio Andreotti later recalled that De Nicola — mainly because of his unique modesty — was not sure whether to accept the nomination, and underwent frequent changes of mind in the face of repeated importuning by all the major political leaders. Andreotti had then to write to him: "Your Excellency, please, decide to decide if you can accept to accept..."

On 25 June 1947, De Nicola resigned from the post, citing health reasons, but the Constituent Assembly immediately re-elected him again the following day, having recognised in his act signs of nobility and humility. After the Italian Constitution took effect, he was formally named the "President of the Italian Republic" on 1 January 1948. He finally refused to be a candidate for the first constitutional election the following May, in which Luigi Einaudi was elected to the Quirinale. De Nicola became a senator for life (as a former Head of State), and later was elected the President of the Senate, and of the Constitutional Court.

He died at Torre del Greco, in the province of Naples, in 1959.