The NAD+ coenzyme was first discovered by British biochemists Arthur Harden and William John Young in 1906. They noticed adding boiled and filtered yeast extract accelerated alcoholic fermentation greatly in unboiled yeast extracts. They called the unidentified factor responsible for this effect a coferment.

Vitamin precursors of NAD+ were identified in 1938, when Conrad Elvehjem showed that live r has an "anti-black tongue" activity in the form of nicotinamide.

Then, in 1939, first strong evidence was found that niacin is used to synthesize NAD+. In the early 1940s, Arthur Kornberg made another important contribution towards understanding NAD+ metabolism, by being the first to detect an enzyme in the biosynthetic pathway.

The metabolism of NAD+ has remained an area of intense research into the 21st century, with interest being heightened after the discovery of the NAD+-dependent protein deacetylases called sirtuins in 2000, by Shin-ichiro Imai and coworkers at the Massachusetts Institute of Technology.