Born in Jacksonville, Florida, Wheeler was educated at Johns Hopkins University, where he obtained his PhD in physics in 1933. After spending the period 1933–35 in Copenhagen working with Niels Bohr, he returned to America to take up a teaching position at the University of North Carolina. In 1938 he went to Princeton, where he served as professor of physics from 1947 until his move to the University of Texas in 1976 to become professor of physics. He retired in 1986.

Wheeler was active in theoretical physics. One of the problems tackled by him was the search for a unified field theory. His earlier papers on the subject were collected in 1962 in his Geometrodynamics. It was here that he introduced the geon (gravitational–electromagnetic entity), with which he aimed to achieve the unification of the two fields. He also collaborated with Richard Feynman in two papers in 1945 and 1949 on the important concept of action at a distance. They formulated a problem that arises when it is accepted that such action cannot take place instantaneously. If X and Y are at rest and one light-minute apart, then any electromagnetic signal emitted by X will reach Y one minute later. This is described by saying X acts on Y by a retarded effect. But by Newton's third law, to each action there corresponds an opposite and equal reaction. This must mean that from Y to X there should also be an advanced effect acting backward in time. Feynman and Wheeler demonstrated how the advance wave could be eliminated from the model to account for the fact that the universe displays only retarded effects.

Wheeler also made important contributions to nuclear physics. With Niels Bohr he put forward an explanation of the mechanism of nuclear fission. He joined the Los Alamos group exploring the possibility of producing an explosive device using heavy hydrogen in 1949–50. Wheeler has provided a popular account of his work in his Journey into Gravity and Spacetime (1990); he has also published his autobiography, At Home in the Universe (1993).