Nikos Hatzikyriakos-Ghika first became involved with painting in Athens, where he studied under Konstantinos Parthenis between 1921 and 1922. In 1922, while in Paris, he began studying French and Greek literature at the Sorbonne. At the same time, he attended courses at the Académie Ranson and at the printmaking workshop of Dimitris Galanis. He remained in the French capital until 1934, making occasional trips back to Greece during this period.

His participation in exhibitions began as early as 1923, when he took part in the Salon des Indépendants in Paris, where he continued to exhibit his work in the following years until 1926. In 1927 he held his first solo exhibition in Paris at the Percier Gallery. The following year he presented his work in Athens, at the Stratigopoulou Hall, in a joint exhibition with the sculptor Michalis Tombros.

Between 1936 and 1937 he collaborated on the publication of the journal To Trito Mati (“The Third Eye”), where he published translations of texts as well as articles. In 1937 he also turned to scenography, designing sets and costumes for a production at the Marika Kotopouli Theatre. This was followed by collaborations with the New School of Dramatic Art of Socratis Karantinos in 1938, and later with the National Theatre (1950), the Greek Modern Ballet of Rallou Manou (1950), the Matey School (1952), and the Royal Opera House, Covent Garden in London (1961).

In 1941 he was elected professor at the School of Architecture of the National Technical University of Athens, where he taught drawing and composition until 1958. In 1946 the first retrospective exhibition of his work was presented at the British Council in Athens, while in 1973 a major retrospective exhibition featuring a total of one hundred and sixty-four works was organized at the National Gallery in Athens.

In 1950 he represented Greece at the Venice Biennale, presenting seventeen works. At the same time, he continued to hold solo exhibitions in major artistic centers such as London, Paris, and Berlin. From 1958 he began collaborating with the Iolas Gallery, through which he exhibited his work in New York, Paris, Geneva, and Milan.

In 1973 Nikos Hatzikyriakos-Ghika was elected a member of the Academy of Athens, and in 1979 he was awarded an honorary doctorate by the School of Architecture of the Aristotle University of Thessaloniki. In 1986 he became a member of the Royal Academy in London. In the same year he made an important donation to the National Gallery, offering forty-five of his works. In 1992, in collaboration with the Benaki Museum, he contributed to the establishment of the Hatzikyriakos-Ghika Museum in Athens. He passed away in 1994 in his birthplace.