He spent the rest of his career at Columbia, becoming the Adrain Professor of Mathematics (1904–27) and Head of the department (1910–16).

Keyser was one of the first Americans to appreciate the new directions in the foundation of mathematics, heralded by the work of Europeans such as Richard Dedekind, Georg Cantor, Giuseppe Peano, Henri Poincaré, David Hilbert, Ernst Zermelo, Bertrand Russell, and A. N. Whitehead.

Alfred Korzybski, founder of general semantics, named Keyser as a major influence.

While at Columbia, Keyser supervised only two PhDs, but they both proved quite consequential: Eric Temple Bell and the logician Emil Post.

Together with the New International Encyclopedia and his Columbia colleague John Dewey, Keyser helped found the American Association of University Professors (AAUP).