Sigma Xi was founded at Cornell University by a junior faculty member and a small group of graduate students in 1886 and is one of the oldest honor societies.

Founded by engineering students and Cornell faculty member, Frank Van Vleck, the society's primary objective was to acknowledge significant scientific research and foster cooperation among scientists from various disciplines.

[12] In the early 20th century, following the 1906 San Francisco earthquake, Sigma Xi's Stanford and Berkeley chapters were involved in reconstruction and public health initiatives.

Notable past presidents of Sigma Xi include Frederick Robbins, a Nobel Prize recipient, and Rita Colwell, the former National Science Foundation Director.

The Greek letters "Sigma" and "Xi" form the acronym of the Society's motto, Σπουδῶν Ξυνῶνες or "Spoudon Xynones," which translates as "Companions in Zealous Research."

Like all "Greek letter" societies, whether professional or social, it is an acronym for the motto of the organization, Σπουδων Ξυνωνες (Spoudon Xynones), which translates as "companions in Zealous Research."

In the early twentieth century, some in the leadership wanted "Sigma Xi" to be dropped altogether in favor of some formulation such as "Scientific Research Society of America."

RESA was a separate entity, wholly owned by Sigma Xi, and represented engineers and scientists at non-academic institutions, such as government and industrial research laboratories.

More than 200 winners of the Nobel Prize have been Sigma Xi members,[17] including Albert Einstein, Enrico Fermi, Richard Feynman, Linus Pauling, Francis Crick, James Watson, Barbara McClintock, John Goodenough, and Jennifer Doudna.