The son of an accountant, Feigenbaum was especially fascinated with how his father's adding machine could reproduce human calculations. Given his early interest in cognition, Feigenbaum's enrollment at the Carnegie Institute of Technology (now Carnegie Mellon University) in Pittsburgh, Pennsylvania, in 1952 placed him in the right place at the right time. After receiving an engineering degree in 1956, he remained to complete a doctorate in 1960 with Herbert Simon (Simon, Herbert A.), one of AI's founding fathers and later a Nobel Prize winner.

Feigenbaum spent the next five years teaching in the business school at the University of California (California, University of), Berkeley. Although his doctoral thesis concerned artificial intelligence, his Ph.D. had been awarded in industrial administration. Dissatisfied by the lack of a computer science program at Berkeley, in 1965 he moved across San Francisco Bay to Stanford University, which proved a much more congenial environment for his AI interests.

On his arrival at Stanford, Feigenbaum founded the Knowledge Systems Laboratory to begin the work for which he would become famous: the development of expert systems (expert system), computer programs that demonstrate the knowledge of a human expert in a specialized domain. Feigenbaum's first major success, DENDRAL (from the Greek word for “tree”), took more than 10 years to develop. Designed in collaboration with the Stanford geneticist Joshua Lederberg (Lederberg, Joshua) and the chemist and inventor of the first commercial oral contraceptive, Carl Djerassi, DENDRAL was intended to aid chemists in determining the structure of organic molecules. Through the use of a complex array of “if-then” rules, DENDRAL generated a “branching tree” to help analyze interstellar mass spectrometry data in the search for evidence of extraterrestrial life. DENDRAL made clear that an expert system is only as good as its rules. To obtain the right rules for an expert system such as DENDRAL, Feigenbaum and his students had to conduct extensive interviews with experts to ascertain the implicit and often unconscious knowledge used in reaching a decision. This interview process acquired the name knowledge engineering, a phrase that captures the essence of the active process of designing an expert system.

Experience with DENDRAL informed the creation of Feigenbaum's next expert system, MYCIN, which assisted physicians in diagnosing blood infections. MYCIN's great accomplishment lay in demonstrating that often the key is not reasoning but knowing. That is, knowing what symptoms correspond to each disease is generally more important than understanding disease etiology. At a basic level, MYCIN also demonstrated that the means of navigating the reasoning tree and the contents of the different branches can be treated separately.

The insights garnered from these early programs allowed expert systems to emerge from the laboratory and into the marketplace as the first successful commercial AI products. Expert systems have played a role in many manufacturing industries as well as the military, as evidenced by Feigenbaum's appointment as the U.S. Air Force chief scientist from 1994 to 1997.

Feigenbaum's autobiographical A Personal View of Expert Systems: Looking Back and Looking Ahead (1992) is an engaging account of his career with many useful references. In 1994 Feigenbaum received the Turing Award from the Association for Computing Machinery.