Born in Fort Scott, Kansas, McCollum was educated at the University of Kansas and at Yale, where he obtained his PhD in 1906. He taught at the University of Wisconsin from 1907 until 1917, when he was appointed to the chair of biochemistry at Johns Hopkins University, a post he retained until his retirement in 1944.

McCollum made a number of advances in the study of vitamins. He was the first, in collaboration with M. Davis in 1913, to demonstrate clearly their multiplicity. They found that rats fed with a diet lacking butterfat failed to develop. They assumed, therefore, the existence of a special factor present in butterfat without which the normal growth process could not take place. As it was clearly fat-soluble, it must be distinct from the antiberiberi factor proposed by Casimir Funk in 1912, which was water-soluble. McCollum named them fat-soluble–A and water-soluble–B, which later became vitamins A and B. In 1920 McCollum was able to extend the alphabet further by naming the antirachitic factor found in cod-liver oil vitamin D (C had already been appropriated to describe the antiscorbutic factor).

McCollum wrote widely on the subject of nutrition, his books including a standard text of the subject, Newer Knowledge of Nutrition (1918), which went through many editions, and A History of Nutrition (1957).