Born in Fort Worth, Texas, Merrifield was educated at the University of California, Los Angeles, where he received his PhD in 1949. He began work immediately at Rockefeller University, New York, and was appointed to the chair of biochemistry in 1966, a post he held until his retirement in 1992.

In the 1950s Merrifield began work on solid-phase peptide synthesis (SPPS). Peptides, like proteins, are composed of chains of amino acids, but have shorter and less complicated chains. Naturally occurring ones possess important physiological properties. The ability to synthesize peptides cheaply and quickly would lead to numerous commercial and medical gains. Yet the synthesis of a polypeptide using traditional methods could take many months.

In peptides the amine end (–NH₂) of one amino acid reacts with the carboxyl end (–COOH) of another. To prepare a pure product of known structure, amino acids have to be coupled in a specific sequence. To achieve this the amine group on one amino acid and carboxyl group on the other must be blocked, so that the other two ends are the ones reacting. And this must be done as each further amino acid is added. In addition, at each stage the product must be isolated and purified. This will involve crystallizing the products. The synthesis of a hundred-unit peptide would involve ninety-nine such procedures. The need for improvement in the technique was painfully clear to peptide chemists.

Merrifield's innovation was to apply an ion-exchange technique by bonding the amino acids, one at a time, to an insoluble solid support. A polystyrene resin was the original choice. As the solid support was insoluble in the various solvents used, all the intermediate products and impurities could be simply washed away by using the appropriate reagent. Much initial work was required in setting up the right kinds of activating agents, blocking agents, and solvents. In 1964 in eight days Merrifield single-handedly synthesized bradykinin, a nine-amino-acid peptide that dilates blood vessels.

One further aspect of Merrifield's process is that it can be fully automated. To demonstrate the power and potential of his method Merrifield undertook in 1965 the automatic synthesis of insulin. With 51 amino acids and two peptide chains held together by two disulfide bridges, the molecule was a formidable challenge. Although more than 5000 operations were involved in assembling the chains, most of these were carried out automatically in a few days. The linking of the two chains, however, was achieved by more traditional methods. The resulting insulin was active in the standard biological assay.

For his development of the technique Merrifield was awarded the 1984 Nobel Prize for chemistry.