He was born in Athens and took his first painting lessons under Konstantinos Parthenis. In 1922, he moved to Paris where he studied in the Academie Ranson, as well as in the studio of Dimitris Galanis. In 1927, he had his first solo exhibition in Paris, while in 1937 he began working on set designs. Between 1941 and 1973, he was teaching in the School of Architecture at the National Technical University of Athens. In 1950, he took part at the Venice Biennale and in 1973 the National Gallery organised a retrospective exhibition of his work. In 1973, he became a member of the Athens Academy and in 1968 a member of the Royal Academy in London. In 1992, he established the Nikos Hadjikyriakos-Ghika Gallery in Athens in collaboration with the Benaki Museum.
An artist with various interests, Ghika was also involved in engraving, book illustration and sculpture. Being a figure of the renowned “30s Generation” in Greece, he was mainly using cubist and constructivist formulations in his painting, to which he was incorporating Greek art elements. His works were at the same time avant-garde and deeply traditional.