Ioannis Kapodistrias was born in Corfu, which at the time of his birth were a possession of Venice . He studied medicine, philosophy and the law at Padua, in Italy. When he was 21 years old, in 1797, he started his medical practice as a doctor in his native island of Corfu. He was throughout his life a deeply liberal thinker and a true democrat, though born and raised as a nobleman. An ancestor of Kapodistrias' had been created a conte (count) by Charles Emmanuel II, Duke of Savoy, and the title was later (1679) inscribed in the Libro d'Oro of the Corfu nobility; the title originates from Capodistria, a city on the eastern shore of the Gulf of Venice. His mother's family, the Gonemi, had been listed in the Libro d'Oro since 1606. In 1802 Ioannis Kapodistrias founded an important scientific and social progress organisation in Corfu, the "National Medical Association". In 1799, when Corfu was briefly occupied by the forces of Russia and Turkey, Kapodistrias was appointed chief medical director of the military hospital.

In 1809 Kapodistrias entered the service of Alexander I of Russia. His first important mission, in November 1813, was as unofficial Russian ambassador to Switzerland, with the task of helping disentangle the country from the French dominance imposed by Napoleon.

He secured Swiss unity, independence and neutrality, which were formally guaranteed by the Great Powers, and actively facilitated the initiation of a new Constitution for the 19 cantons that were the component states of Switzerland, with personal drafts. In the ensuing Congress of Vienna, 1815, as the Russian minister, he counterbalanced the paramount influence of the Austrian minister, and insisted on French state unity under a Bourbon monarch.

Ioannis Kapodistrias retired to Geneva, where he was greatly esteemed, having been made an Honorary Citizen for his past services to Swiss unity and particularly to the cantons. In 1827, he learned that the newly-formed Greek National Assembly had, as he was the most illustrious Greek-born politician in Europe, elected him as the first head of state of newly-liberated Greece, with the title of Kivernetis .After touring Europe to rally support for the Greek cause, Kapodistrias landed in Nafplion 7 January 1828 and arrived in Aegina on 8 January 1828.

It was the first time he had ever set foot on the Greek mainland, and he found a discouraging situation there. Even while fighting against theOttomans was still going on, factional and dynastic conflicts had led to two civil wars which ravaged the country. Greece was bankrupt and the Greeks were unable to form a united national government.

From the first capital of Greece, Aegina, he ushered in a new era in the country, which had just been liberated from a 400 year Turkish occupation. He founded schools, established Foundations for young women to work and inaugurated the first university. These Institutes educated the first teachers of liberated Greece.

On his arrival, Kapodistrias launched a major reform and modernisation programme that covered all areas. He re-established military unity, bringing an end to the second phase of the civil war; re-organised the military, which was then able to reconquer territory lost to the Ottoman military during the civil wars; introduced the first modern quarantine system in Greece, which brought epidemics like typhoid fever, cholera and dysentery under control for the first time since the start of the War of Independence; negotiated with the Great Powers and the Ottoman Empire the borders and the degree of independence of the Greek state and signed the peace treaty that ended the War of Independence with the Ottomans; introduced the phoenix, the first modern Greek currency; organised local administration; and, in an effort to raise the living standards of the population, introduced the cultivation of the potato into Greece.

In 1831, Kapodistrias ordered the imprisonment of Petrobey Mavromichalis, the Bey of the Mani Peninsula, one of the wildest and most rebellious parts of Greece. This was a mortal offence to the Mavromichalis family, and on October 9, 1831 he  was assassinated by Petrobey's brother Konstantis and son Georgios on the steps of the church of Saint Spyridon in Nafplio. Kapodistrias woke up early in the morning and decided to go to church despite the urges of his servants and bodyguards to stay at home. When he reached the church he saw his assassins waiting outside and continued walking towards the entrance. When he reached them Konstantis and Georgios came close to him to greet him and suddenly Konstantis drew his pistol and fired at him but he missed and the bullet stuck in the church's wall where it is still visible today.

Kapodistrias is greatly honoured in Greece today. The University of Athens is named "Kapodistrian" in his honour; the Greek euro coin of 20 cents bears his face, as did the 500 drachmas banknote before the introduction of the euro, and a local re-organisation programme that reduced the number of municipalities in the late 1990s also carries his name. The fears that Britain, France and Russia had of any liberal and Republican movement at the time, due to the Reign of Terror in the French Revolution, led them to insist on Greece becoming a monarchy after Kapodistria's death.His summer home in Koukouritsa, Corfu has been converted to a museum commemorating his life and accomplishments and has been named Kapodistrias Museum in his honour. It was donated by the late Maria Desylla-Kapodistria, grand niece of Ioannis Kapodistrias, to three cultural societies in Corfu.

In 2001 in the city Capo d'Istria of Slovenia a lifesize statue of Ioannis Kapodistrias was unveiled in the central square of the city. The square was renamed after Kapodistrias, since Koper was the place of Kapodistrias' ancestors before they moved to Corfu in the 14th century. Greek sculptor K. Palaiologos created the statue and he transported it  to Koper with a ship of the Greek Navy. The ceremony was attended by the Greek ambassador and Eleni Koukou, a Kapodistrias scholar and professor at the National and Kapodistrian University of Athens .