Lewis, born the son of a lawyer in Weymouth, Massachusetts, was educated at the University of Nebraska and at Harvard, where he obtained his PhD in 1899. After a period abroad at Göttingen and Leipzig he returned to teach at Harvard and the Massachusetts Institute of Technology until 1912, when he moved to the University of California at Berkeley to take up an appointment as professor of physical chemistry.

In about 1916 he first introduced the notion of a covalent bond, in which the chemical combination between two atoms derives from the sharing of a pair of electrons, with one electron contributed by each atom. This was part of Lewis's more general octet theory and he published his views in Valence and the Structure of Atoms and Molecules (1923). Here he proposed that the electrons in an atom are arranged in concentric cubes and that a neutral atom of each element contains one more electron than a neutral atom of the element preceding it. The cube of eight electrons is reached in the atoms of the rare gases.

These simple ideas enabled Lewis to explain many of the facts of chemical combination. Thus neon and argon with all vertices of the cube occupied are obviously inert, having no space to interact with other atoms. The tendency is for other atoms to attain the same configuration. Thus sodium with one vertex occupied will react readily with the seven occupied vertices of chlorine to produce a combination with all vertices occupied. And so, with considerable success, Lewis went on to explain the basic combinations of the lighter elements.

The theory became widely known as the Lewis–Langmuir theory. This was partly due to the failure of Lewis, a shy and reserved man, to publicize his theory and the willingness of Irving Langmuir, a brilliant lecturer, to fill the gap.

Lewis also carried out significant work in the field of chemical thermodynamics and published, with Merle Randall, Thermodynamics and the Free Energy of Chemical Substances (1923), which did much to introduce the basic ideas of Josiah Willard Gibbs to a generation of students. He is also known for his general theory of acids and bases (1923): a Lewis acid is a substance that can donate an electron pair; a Lewis base is one that can accept a pair of electrons.