Born the son of Johanna Chevalier, he was a descendant of the French Huguenots. Appel began painting at the age of 14. His first work was a still life of a fruit basket. During the German occupation, he studied at the Rijksakademie van Beeldende Kunsten in Amsterdam from 1940-1943. Here he also met Corneille and Constant.

In 1946, Karel Appel had his first show in Groningen. In 1947, Appel joined the Experimental Group, along with Anton Rooskens, Jan Nieuwenhuys and Theo Wolvecamp.

In 1948, Karel Appel was one of the founders of the avant-garde CoBrA movement. A year later, in 1949, he and the other CoBrA artists participated in a group exhibition at the Stedelijk Museum in Amsterdam that led to many objections from the public and the press. Appel used this to his advantage; his fresco "Questioning Children," which he commissioned for the Amsterdam City Hall, was covered up for 10 years after it led to controversy.

Karel Appel was influenced by Pablo Picasso, Henri Matisse and Jean Dubuffet, and following the controversy, Appel moved to Paris in 1950, followed by Mexico, the United States, Brazil and Italy. After 1990, Appel regained popularity in the Netherlands and received several major shows organized by Rudy Fuchs and the CoBrA Museum.

Karel Appel's work was exhibited in a number of renowned galleries worldwide, including the Anita Shapolsky Gallery in New York, Galerie Lelong in Paris and Galerie Ulysses in Vienna.

Karel Appel died on May 3, 2006 at his home in Zurich, Switzerland.

Karel Appel's work is held in many public collections including the Museum de Fundatie, Zwolle, Netherlands, the Art Gallery of Hamilton , Ontario, Canada and the Rijksmuseum in Amsterdam.