He took his first painting courses in Athens under Konstantinos Parthenis (1921-1922). In 1922, in Paris, he enrolled at the Sorbonne to study French and Greek literature, while also attending classes at the Académie Ranson and the engraving studio of Dimitris Galanis. He remained in the French capital until 1934, all the while taking several trips back to Greece. He began his exhibition activity as early as 1923, when he joined the Salon des Indépendants, exhibiting with them until 1926. In 1927 he held his first solo show in Paris, at Galerie Percier, and the following year he exhibited in Athens, at the Stratigopoulos gallery, together with sculptor Michalis Tombros. In 1936-1937, he contributed translations and articles in the publication of the Greek journal To Trito Mati (The Third Eye). In 1937, he began his involvement with stage design, designing the sets and costumes for a performance of the Marika Kotopouli Theater. This was followed by his collaboration 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 Matey School (1952) and the Covent Garden in London (1961). In 1941 he was elected Professor at the National Technical University of Athens School of Architecture, where he taught drawing and composition until 1958. 1946 marked the year of his first retrospective exhibition, held at the British Council in Athens, followed, in 1973, by the retrospective at the National Gallery of Athens, featuring one hundred and sixty-four of his works. In 1949 he exhibited with the group “Armos” (Junction), of which he was a founding member, and in 1950 he participated in the Venice Biennale with seventeen works. In the meantime he continued to hold solo shows in many cities, such as London, Paris and Berlin, and in 1958 he began his association with Iolas gallery, exhibiting in New York, Paris, Geneva and Milan. In 1973 he was elected a member of the Academy of Athens, in 1979 he was awarded an honorary doctorate by the Aristotle University of Thessaloniki School of Architecture, and in 1986 he was elected a member of the Royal Academy of London. That same year, the artist donated forty-five of his works to the Greek National Gallery. In 1992, he founded, in cooperation with the Benaki Museum, the Hadjikyriakos-Ghikas Museum in Athens.
A man of diverse intellectual and artistic interests, he was also active in engraving, book illustration and sculpture – a retrospective exhibition of his sculptural work was held in 1984 at the gallery “To Trito Mati” (The Third Eye) in Athens – while he also gave many lectures and published studies and articles on art and aesthetics. A prominent figure of the renowned “Generation of the ’30s”, Ghikas employed cubist and constructivist formulations in his painting, combining them with various types of Greek art, thus achieving a purely personal amalgam of the European avant-garde and local traditional elements.