Van Vleck was born at Middletown, Connecticut, and educated at the University of Wisconsin, where he graduated in 1920. Moving to Harvard University he gained his master's degree (1921) and his doctorate (1922) and stayed for a further year as an instructor. From Harvard he went to the University of Minnesota, where he became a full professor in 1927, returned to Wisconsin in 1928, and then went back to Harvard in 1934.

Van Vleck is regarded as the founder of the modern quantum mechanical theory of magnetism. His earliest papers were on the old quantum theory, but with the advent of wave mechanics pioneered by Paul Dirac he began to look at the implications for magnetism in particular. In the field of paramagnetism he introduced the concept of temperature-independent susceptibility, now known as Van Vleck paramagnetism. He also made calculations of molecular structure that shed new light on chemical bonding and he developed ways of describing the behavior of an atom or an ion in a crystal. Another important contribution of Van Vleck was to point out the importance of electron correlation – the interaction between the motion of electrons – for the appearance of local magnetic moments in metals.

During World War II Van Vleck worked on radar, showing that at about 1.25-centimeter wavelength water molecules in the atmosphere would lead to troublesome absorption and that at 0.5-centimeter wavelength there would be a similar absorption by oxygen molecules. This was to have important consequences not just for military (and civil) radar systems but later for the new science of radioastronomy.

In 1977, together with Nevill Mott and Philip Anderson, he shared the Nobel Prize for physics for “fundamental theoretical investigations of the electronic structure of magnetic and disordered systems.” (Anderson was once a student of Van Vleck's at Harvard.) Van Vleck's work on electron correlation was mentioned specifically for the central role it played in the later development of the laser.