He was born in the town of Velventos in Kozani. As a youth he moved to Bucharest where he studied at the Greek School. On 1821 he fought at the insurrection against the Turks led by Alexander Ypsilanti and was captured at the Battle of Dragashani. After escaping, he traveled to Vienna, and then to Leipzig, where he studied architecture. Afterwards he pursued his studies further in Berlin with Karl Friedrich Schinkel.
After graduation, he returned with his colleague and friend Eduard Schaubert to Greece, where they were appointed public engineers by John Capodistria. On 1832 they created a new city plan for Athens, which included wide avenues, gardens and grand public buildings and gave the first street names in Athens. This plan was however was simplified by Leo von Klenze, as it was considered too expensive. After disagreements with the administration, Kleanthis resigned his position.
Kleanthis gained great wealth not only through architecture, but also through the marble quarries he operated on the island of Paros. Marble from his quarries received a gold medal at the London Great Exhibition.
On 1862 he was seriously injured in an accident in a quarry and he was transported to Athens, where he died.
Kleanthis designed many important buildings in Athens, including the Dutchess of Plaisance's mansion, Villa Ilissia (today the Byzantine Museum of Athens). The University of Athens was initially accommodated in his house in Plaka, which now houses the Athens University Museum.
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