His first major contribution was a theory of approximate molecular orbital (MO) calculations on pi electron systems in 1953, identical to the one developed by Rudolph Pariser and Robert G. Parr in the same year, and now called the Pariser-Parr-Pople (PPP) method. Subsequently, he developed the methods of Complete Neglect of Differential Overlap (CNDO) (in 1965) and Intermediate Neglect of Differential Overlap (INDO) (shortly later) for approximate MO calculations on three-dimensional molecules, and other developments in computational chemistry. He pioneered the development of more sophisticated computational methods, so called ab initio methods, that used basis sets of either Slater type orbitals or Gaussian orbitals to model the wave function. While in the early days these calculations were extremely expensive to perform, the advent of high speed microprocessors has made them much more feasible today. He was instrumental in the development of one of the most widely used computational chemistry packages, the "Gaussian(tm)" suite of programs.

In 1986 he moved from Carnegie-Mellon University in Pittsburgh, Pennsylvania, where his earlier accomplishments were made, to Northwestern University in Chicago, Illinois, where he is now a professor.

He received the Nobel Prize in Chemistry in 1998.