He took his first painting lessons in Athens, under Konstantinos Parthenis(1921-1922). In 1922 he was in Paris and enrolled at the Sorbonneto study French and Greek literature while at the same time also enrolling at the Ranson Academy and the engraving studio of Dimitris Galanis. He remained in the French capital till 1934, making trips to Greece during his residence. He had already begun to exhibit by 1923 when he participated in the Salon des Independents, where he also exhibited in the coming years, until 1926, while from 1930 to 1934 he took part in the Salon des Surindependents. In 1927 he had his first solo show in Paris at the Percier gallery and the following year at the Stratigopoulos gallery in Athens, along with the sculptor Michalis Tombros. In 1936-1937 he worked on the publication of the Greek magazine Το Τρίτο Μάτι in which he published translations of texts and articles. In 1937 he commenced his involvement with stage design, designing sets and costumes for performances of the Marika Kotopouli Theater. This was followed by cooperative endeavors with the New School of Dramatic Art run by Sokratis Karantinos (1938), the National Theater (1950), the Modern Greek Ballet of Rallou Manou (1950), the Matei School (1952) and Covent Garden in London (1961). In 1941 he was elected Professor at the School of Architecture of the National Technical University where he taught drawing and composition till 1958. In 1946 the first retrospective exhibition of his work was held at the British Council in Athens and this was followed, in 1973, by the retrospective at the National Gallery of Athens with one hundred and sixty four of his works. In 1949 he exhibited with the Junction group, of which he was a founding member, and in 1950 participated in the Venice Biennale with seventeen works. In the meantime he continued to have solo shows in many cities such as London, Paris and Berlin and in 1958 he began his association with the Iolas gallery, exhibiting in New York, Paris, Geneva and Milan. In 1973 he was elected a member of the Athens Academy and in 1979 was proclaimed honorary doctor of the Architectural School of the Aristotelian University of Thessaloniki while in 1986 he was elected a member of the Royal Academy of London. The same year the artist donated forty-five of his works to the National Gallery. In 1992, in cooperation with the Benaki Museum, the Chatzikyriakos-Ghika Museum was founded in Athens.
A person with a variety of intellectual and artistic interests, he was also involved with engraving, book illustration and sculpture — a retrospective exhibition of his sculptural work was held in 1984 at the Trito Mati gallery in Athens — while he also gave many lectures and published studies and articles on art and aesthetics. A figure of the renowned “”Thirties Generation”” in Greece, Ghika developed cubist and constructivist formulations in his painting, which he used in combination with various types of Greek art, thus achieving a purely personal amalgam of the European avant garde and indigenous traditional elements.