He relocated to Berlin in 1923, where he became friendly with members of the influential November Group. That same year, he painted his first painting without a subject, a composition of vertical and horizontal lines and planes. His first solo exhibition was held in 1924, at the Galeria d'Audretsch. In 1925, he became the youngest member of De Stijl, working closely with the famed Theo van Doesburg and Piet Mondrian. His work in this period often straddled several mediums. He concentrated on three-dimensional reliefs, often incorporating pieces of Plexiglas and metal as well as photomontages and cutouts from advertisements. Though he opened a silkscreen process studio for printmaking in 1934, relief was still his favorite medium and he developed the medium to a high art form. In 1936, he took part in an exhibition of Cubism and Abstract Art in the Museum of Modern Art in New York City.
Domela also experimented with typography and was commissioned to produce advertisements in Germany. When Hitler came into power in 1933, Domela fled Berlin and resettled in Paris, where he remained until his death in 1992. He was also forced to destroy a large part of his library, as it contained numerous books written by 'anarchists', many of which he had designed the books for