He was born in Ciudad Bolívar, Venezuela. He began his artistic career as a boy painting cinema posters in his native city. He received his artistic training in Caracas. He directed the Escuela de Artes Plasticas in Maracaibo from 1947 to 1950, when he left for Paris and began associating with Yaacov Agam, Jean Tinguely, Victor Vasarely, and other artists connected with the Salon des Realités Nouvelles and the Galerie Denise René. Soto's breakthrough works of the 1950s and 1960s were "geometric abstract paintings, using a limited and carefully selected array of flat colors."

Soto has created penetrables, interactive sculptures which consist of square arrays of thin, dangling tubes through which observers can walk. It has been said of Soto's art that it is inseparable from the viewer; it can only stand completed in the illusion perceived by the mind as a result of observing the piece.

From 1970 until the early 1990s, Soto's works appeared in places such as the Museum of Modern Art and the Guggenheim Museum in New York City, as well as the Centre Georges Pompidou in Paris.

In 1973, the Jesús Soto Museum of Modern Art opened in Ciudad Bolívar, Venezuela with a collection of his work. The Venezuelan architect Carlos Raúl Villanueva designed the building for the museum and the Italian op artist Getulio Alviani was called to direct it. Unlike conventional art galleries, a large number of the exhibits are wired to the electricity supply so that they can move.

Some of Soto's work adorns Caracas' main arts centre, the Teresa Carreño Cultural Complex.

Jesús Rafael Soto died in 2005 in Paris, and is buried in the Cimetière du Montparnasse.