Witten was born in Baltimore, Maryland. Having graduated from Brandeis College, Massachusetts, in 1971 with a degree in history, he intended to pursue a career in journalism. However, after working on George McGovern's 1972 presidential campaign, he realized that he was ill-suited to the world of political journalism and returned to university to study physics at Princeton. After completing his PhD in 1976 Witten remained at Princeton, where he was appointed professor of physics – a post he occupied until 1987 when he moved to the Institute for Advanced Study.

Witten has worked mainly in the development of string theory. In the 1960s Yoichiro Nambu and others had shown that elementary particles could be treated as strings of a certain kind, but it was soon shown that the theory only worked satisfactorily in 26 dimensions. A more ambitious theory of superstrings was promoted by Mike Green and others in the 1970s. When Witten came across the theory in 1975 he saw that it could throw light on what he termed “the single biggest puzzle in physics,” namely, how to unify general relativity, which deals with gravity and space, with quantum mechanics, which explains events at the nuclear level. The realization in 1982 that superstring theory demanded the presence of gravity in its working was, for Witten, “the greatest intellectual thrill of my life.” In the early 1980s Witten ruled out string theories in 11 dimensions derived from models based on the approach of Theodor Kaluza and Oskar Klein. Further, he argued that a number of mathematical anomalies would emerge in spaces with two, six, or ten dimensions. In 1984, however, Green and John Schwarz were able to show that, under certain special assumptions, a theory of ten dimensions could be developed that avoided the anomalies and explained the existence of particles with a built-in handedness (termed chirality).

Witten then began work showing how, in a ten-dimensional universe, the hidden extra six dimensions could be compacted and how they could interact with particles in detectable ways. He has sought for an analysis, based on geometric foundations, and has attempted to develop a topological quantum-field theory that gives due regard to the fundamental geometrical properties of matter. Witten's work is important in pure mathematics as well as in physics. In 1990 he was awarded the Fields Medal (regarded as the mathematics equivalent of a Nobel prize).

Some critics, including the Nobel laureate Sheldon Glashow, have objected that Witten's work has nothing to do with physics and is merely mathematical, while being impenetrable at the same time. Witten has replied that the theory has not been fully worked out yet and that it may well be many years before a precise description of nature can be offered. He has described string theory as “a 21st-century theory that has dropped by accident into the 20th century.” Glashow replied: “Please heed our advice that you too are not smitten; The book's not finished, the last word is not Witten.”