Post had been interested in astronomy, but at the age of twelve lost his left arm in a car accident. This loss was a significant obstacle to being a professional astronomer. He decided to pursue mathematics, rather than astronomy.
After completing his Ph.D. in mathematics at Columbia University, supervised by Cassius Jackson Keyser, he did a post-doctorate at Princeton University in the 1920–1921 academic year. Post then became a high school mathematics teacher in New York City.
Post married Gertrude Singer in 1929, with whom he had a daughter, Phyllis Goodman. Post spent at most three hours a day on research on the advice of his doctor in order to avoid manic attacks, which he had been experiencing since his year at Princeton.
In his doctoral thesis, later shortened and published as "Introduction to a General Theory of Elementary Propositions" (1921), Post proved, among other things, that the propositional calculus of Principia Mathematica was complete: all tautologies are theorems, given the Principia axioms and the rules of substitution and modus ponens. Post also devised truth tables independently of Wittgenstein and C.S. Peirce and put them to good mathematical use. Jean Van Heijenoort's well-known source book on mathematical logic (1966) reprinted Post's classic article setting out these results.
While at Princeton, Post came very close to discovering the incompleteness of Principia Mathematica, which Kurt Gödel proved in 1931. Post initially failed to publish his ideas as he believed he needed a 'complete analysis' for them to be accepted.
In 1936, Post developed, independently of Alan Turing, a mathematical model of computation that was essentially equivalent to the Turing machine model. Intending this as the first of a series of models of equivalent power but increasing complexity, he titled his paper Formulation 1. This model is sometimes called "Post's machine" or a Post–Turing machine, but is not to be confused with Post's tag machines or other special kinds of Post canonical system, a computational model using string rewriting and developed by Post in the 1920s but first published in 1943. Post's rewrite technique is now ubiquitous in programming language specification and design, and so with Church's lambda-calculus is a salient influence of classical modern logic on practical computing. Post devised a method of 'auxiliary symbols' by which he could canonically represent any Post-generative language, and indeed any computable function or set at all.
In an influential address to the American Mathematical Society in 1944, he raised the question of the existence of an uncomputable recursively enumerable set whose Turing degree is less than that of the halting problem. This question, which became known as Post's problem, stimulated much research. It was solved in the affirmative in the 1950s by the introduction of the powerful priority method in recursion theory.
Post made a fundamental and still-influential contribution to the theory of polyadic, or n-ary, groups in a long paper published in 1940. His major theorem showed that a polyadic group is the iterated multiplication of elements of a normal subgroup of a group, such that the quotient group is cyclic of order n − 1. He also demonstrated that a polyadic group operation on a set can be expressed in terms of a group operation on the same set. The paper contains many other important results.