Hess, who was born at Geneva in Switzerland, was taken to Russia as a child by his parents. He studied medicine at the University of Dorpat (1822–25) and started his career by practicing medicine in Irkutsk. In 1830 he moved to St. Petersburg, becoming professor of chemistry at the Technological Institute of the university. While there he wrote a chemistry textbook in Russian, which became a standard work.

Hess worked on minerals and on sugars, but his main work was on the theory of heat. By carefully measuring the heat given off in various chemical changes, he was able to conclude in 1840 that in any chemical reaction, regardless of how many stages there are, the amount of heat developed in the overall reaction is constant. Hess's law, also called the law of constant heat summation, is in fact a special case of the law of conservation of energy.