In the early years of his marriage de Ménil was a banker, serving as vice-president (1932–1938) of the Banque Nationale pour le Commerce et l'Industrie in Paris.

[1][6] John and Dominique de Ménil began collecting art intensively in the 1940s, beginning with a purchase of Paul Cézanne's 1895 painting Montagne (Mountain) in 1945.

The de Ménils' Catholic faith, especially their interest in Father Yves Marie Joseph Congar's teachings on ecumenism, would become crucial in the development of their collecting ethos in the coming decades.

[1] With the guidance of the Dominican priest Marie-Alain Couturier, who introduced the de Ménils to the work of artists in galleries and museums in New York, they became interested in the intersection of modern art and spirituality.

[8] The de Ménils were particularly interested in modern European art, and a core strength of the collection was the many Cubist, Surrealist, and other Modernist works they acquired.

[9] Over the years the family enjoyed close personal friendships with many of the artists whose work they collected, including Victor Brauner, Max Ernst, Jasper Johns, Yves Klein, René Magritte, Robert Rauschenberg, Dorothea Tanning, and Andy Warhol.

In 1949 John and Dominique de Menil commissioned the architect Philip Johnson to design their home in the River Oaks neighborhood in Houston.

One of the first International style residences in Texas, it generated controversy not only by standing out amongst the mansions of River Oaks but also by pairing Johnson's clean, modernist lines with a bold color palette and eclectic interior design by Charles James.

"[16] In 1954 they founded the Menil Foundation, a non-profit organization dedicated to the "support and advancement of religious, charitable, literary, scientific and educational purposes.

[1] They worked with such noted filmmakers as Roberto Rossellini, who made several trips to Houston to teach Rice University students and create television documentaries.

[18] Other filmmakers who visited the Media Center included Ola Balogun, Bernardo Bertolucci, James Blue, Jim McBride, and Colin Young.

John and Dominique de Menil also shared an interest in photography, inviting photographers to come to Houston to document events in the city and exhibit their work.

An ongoing project that seeks to catalogue and study the depiction of individuals of African descent in Western art, it is now under the aegis of Harvard University.

[20] Their most controversial action on behalf of civil rights was their offer of Barnett Newman's Broken Obelisk as a partial gift to the city of Houston in 1969, on the condition that it be dedicated to the recently assassinated Dr. Martin Luther King Jr.[21] The city refused the gift, sparking a controversial debate[22] that involved de Menil proposing that the sculpture be inscribed with the Biblical quote "Forgive them for they know not what they do.

[25] It was established as an autonomous organization the next year and began hosting colloquia, beginning with "Traditional Modes of Contemplation and Action," which brought together religious leaders, scholars, and musicians from four continents.