Throughout a nearly six-decade career, Appel pushed his studio practice to extremes, often shifting between abstraction and figuration, never content to settle on one signature style, media, or body of work. His earliest works, created during the time he co-founded the COBRA group with Asger Jorn, Christian Dotremont, and Constant, make evident his interest in the uninhibited artistic experience. As a member of the Dutch Experimental Group and later Art Informel, Appel drew his earliest and possibly greatest inspiration from folk art, children's drawings, and the works of the mentally disturbed. This is perhaps most clear in The Psychopathological Notebook, a collection of free-form drawings on pages of catalogue text from the International Exhibition on Psychopathological Art, 1950 at the Saint-Anne Hospital for the mentally ill in Paris. Visiting this exhibition on multiple occasions proved impactful for Appel and would inform much of his work in the following years.

At the suggestion of French critic Michel Tapié, Appel met gallerist Martha Jackson, who would give the artist his first one-person show in New York City in 1954 and continue to show his work for the next twenty years. During his time in New York in the late 1950s, Appel became friendly with Sam Francis, Jackson Pollock, fellow-Dutchman Willem DeKooning, Franz Kline, and other members of the Abstract Expressionist group, as well as Jazz luminaries Dizzie Gillespie, Miles Davis, Count Basie, and Sarah Vaughan. This circle of cultural producers was sympathetic to Appel's interest in a self-conscious investigation of the psychology of painting and would influence the artist's shift from realism to an emotionally charged, robustly active, and spontaneous abstract painting style. Having already begun with his peers in COBRA to explore an anticlassical stance in favor of what critic Hal Foster has termed the 'creaturely' — a 'pagan vernacular of the North in opposition to the official Christianity of the South' — Appel's time in New York allowed him to propel towards a de-aestheticised, boundless expressivity.

Appel spent much of the following half-century moving between New York and Europe. During his lifetime, the artist would participate in numerous one-person traveling exhibitions around the world and would represent the Netherlands in the 27^th International Art Exhibition in the Venice Biennale.