Hoagland was born in Boston, Massachusetts, the son of Hudson Hoagland, a distinguished neurophysiologist. Having obtained his MD from Harvard in 1948, he joined the Huntington Laboratories of the Massachusetts General Hospital. He then served in the Harvard Medical School from 1960 until 1967 when he became professor of biochemistry at Dartmouth. From 1970 to 1985 he was scientific director of the Worcester Institute for Experimental Biology, founded by his father and Gregory Pincus in 1944.

In early 1955 Francis Crick published his ‘adaptor’ hypothesis to explain protein synthesis by the cell. Unaware of this work, Hoagland, in collaboration with Paul Zamecnick and Mary Stephenson, provided the experimental confirmation in 1956. It had earlier been shown by George Palade that protein synthesis occurred outside the nucleus in the ribosomes. Hoagland and Zamecnick discovered that before the amino acids reach the ribosomes to be synthesized into protein, they are first activated by forming a bond with the energy-rich adenosine triphosphate (ATP).

What happened in the ribosome was unveiled by forming a cell-free mixture of ATP, the radioactively labeled amino acid leucine, enzymes, and some of the small soluble RNA molecules found in the cytoplasm. At this point they discovered the crucial step, predicted by Crick, in between the activation of the amino acid and its appearance in the protein; the amino acid became tightly bound to the soluble RNA. Shortly afterward the labeled leucine was no longer bound to the RNA but present in the protein. The discovery of transfer RNA (or tRNA as it soon became known) was also made independently by Paul Berg and Robert Holley.

In his autobiography Toward the Habit of Truth (1990), Hoagland described his work as a molecular biologist and sketched the history of the Worcester Institute.