Constantine gained his fame during the Greek War of Independence (1821–1829). Unlike most other prominent figures of the War, he had never been initiated in to the Filiki Eteria (Friendly Society), which played a significant role in the revolution against the Ottoman Empire, primarily by secret recruitment of supporters against the Empire.

By early 1821, it had gained enough support to declare a revolution. This declaration seems to have surprised Constantine, who was absent at Odessa. He returned to Psara in haste and was there when the island joined the Revolution on April 10, 1821.

The island formed its own fleet of ships and the famed seamen of Psara, already known for their successful naval combats against pirates and their well-equipped ships, proved to be effective at full naval war. Constantine soon distinguished himself as a fire ship captain.

       

The destruction of the Ottoman flagship at Chios by Kanaris.

At Chios, on the night of June 6/June 7, 1822 forces under his command destroyed the flagship of the Turkish admiral Nasuhzade Ali Pasha (or Kara-Ali Pasha) in revenge for the Chios Massacre. The admiral was holding a celebration, while Kanaris and his men managed to place a fire ship next to it. When the flagship's powder store caught fire, all men aboard were instantly killed. The Ottoman casualties comprised 2000 men, both naval officers and common sailors, as well as Kara-Ali himself.

Constantine led three further successful attacks against the Turkish fleet in 1822–1824. He was famously said to have encouraged himself by murmuring "Konstantí, you are going to die" every time he was approaching a Turkish warship on the fire boat he was about to detonate.

Egypt was technically a province of the Ottoman Empire at the time but its viceroy Mohammad Ali (1769–1849), had earned enough power to act independently from the Sultan and had formed his own army and naval fleet. It was headed by his adoptive son Ibrahim Pasha (1789–1848). The latter had hired a number of veteran French officers - who had served under Emperor Napoleon I and were discharged from the French army following his defeat - to help organise the new army. By 1824, it counted 100,000 men and was both better organised and better equipped than the Sultan's army.

Sultan Mahmud II offered to the viceroy the command of Crete, if he agreed to send part of this army against the Greeks. They quickly reached an agreement. The Egyptian army, under the personal command of Ibrahim Pasha, started a campaign in both land and sea against the Greeks.

After the destruction of his home island, Constantine continued to lead his men into attacks against the Turks, until the Battle of Navarino of October 20, 1827. Then the Turkish-Egyptian fleet was destroyed by the combined naval forces of Britain, France and Russia.

Following the end of the war and the independence of Greece, Constantine became an officer of the new Greek Navy, reaching the rank of Admiral, and later became a prominent politician.