Born in Pittsburgh, Pennsylvania, Hench was educated at Lafayette College and the University of Pittsburgh, where he obtained his MD in 1920. He spent most of his career working at the Mayo Clinic, becoming head of the section for rheumatic diseases in 1926. Hench was also connected with the Mayo Foundation and the University of Minnesota, where he became professor of medicine in 1947.

For many years Hench had been seeking a method of treating the crippling and painful complaint of rheumatoid arthritis. He suspected that it was not a conventional microbial infection since, among other features, it was relieved by pregnancy and jaundice. Hench therefore felt it was more likely to result from a biochemical disturbance that is transiently corrected by some incidental biological change. The search, he argued, must concentrate on something patients with jaundice had in common with pregnant women. At length he was led to suppose that the antirheumatic substance might be an adrenal hormone, since temporary remissions are often induced by procedures that stimulate the adrenal cortex. Thus in 1948 he was ready to try the newly prepared ‘compound E’, later known as cortisone, of Edward Kendall on 14 patients. All showed remarkable improvement, which was reversed on withdrawing the drug.

For this development of the first steroid drug Hench shared the 1950 Nobel Prize for physiology or medicine with Kendall and Tadeus Reichstein.