His work has elements of the mid-20th-century New York artistic experience such as Surrealist and Abstract Expressionist and figurative aspects across several media such as watercolor, oil, and acrylic as well as etchings, lithographs and monoprints.

He worked in the WPA Graphic Arts Workshop (Print Section) in Philadelphia alongside Roswell Weidner, Dox Thrash and Michael Gallagher.

[8] By the late 1930s, Mesibov's work displayed aspects of social commentary and current events with cubist, surrealist and modernist elements, such as his abhorrence of war's destruction in "Bombing of Nanking".

His first New York one-man show in 1947 was at the Chinese Gallery, of increasingly cubist and abstract work in his preferred medium acrylic on canvas.

During the late 1940s, he opened a studio in Newark, NJ with a fellow New York and Philadelphia ceramicist, Frances Serber, [13] and shared exhibition spaces with Milton Avery, Nell Blaine, Ralph Rosenborg, John Ferron and Boris Margo.

He also formed professional relationships with Jackson Pollock, Willem de Kooning, Philip Guston, Adolph Gottlieb, Robert Motherwell, Barnett Newman, Ad Reinhardt and Mark Rothko.

Inspired by Samuel Taylor Coleridge's Rime of the Ancient Mariner and Miguel de Cervantes Saavedra's Don Quixote, he produced a series based on each.

In 1972, Mesibov was commissioned to paint a mural for the Temple Beth El in Spring Valley, New York, which was composed of three combined canvases each measuring 6 by 16 feet (1.8 by 4.9 m).