After graduating from Johns Hopkins, Flexner returned to Louisville and founded a private school in which to test his ideas about education. He believed that education should be marked by small classes, personal attention, and hands-on teaching. Graduates of his school were soon accepted at leading colleges, and Flexner's school attracted considerable attention.
Between 1912 to 1925, Flexner served on the Rockefeller Foundation's General Education Board, and after 1917 was its secretary. With the help of the Board, he founded another experimental school, the Lincoln School, which opened in 1917, in cooperation with the faculty at Teachers College of Columbia University.
In 1908, Flexner published his first book, The American College. Strongly critical of many aspects American higher education, it was especially critical of the university lecture as a method of instruction. According to Flexner, lectures enabled colleges to "handle cheaply by wholesale a large body of students that would be otherwise unmanageable and thus give the lecturer time for research."
Flexner's book attracted the attention of Henry Pritchett, president of the Carnegie Foundation, who was looking for someone to lead a series of studies of professional education. Although Flexner had never set foot inside a medical school, Flexner was Pritchett's first choice to lead a study of American medical education. Thus Flexner joined the research staff at the Carnegie Foundation in 1908. Two years later, he published the Flexner Report, which examined the state of American medical education and led to far-reaching reforms in the way doctors were trained. The Flexner report led to the closure of most rural medical schools and all but two of America's African American medical colleges. Ironically one of the schools was located in his own hometown of Louisville, Louisville National Medical College.
Flexner soon conducted a related study of medical education in Europe. According to Bonner (2002), Flexner's work came to be "nearly as well known in Europe as in America." With funding from the Rockefeller Foundation, he worked toward restructuring the nation's medical schools. Flexner (Bonner 2002) "...exerted a decisive influence on the course of medical training and left an enduring mark on some of the nation's most renowned schools of medicine." Flexner worried that "the imposition of rigid standards by accrediting groups was making the medical curriculum a monstrosity," with medical students moving through it with "little time to stop, read, work or think." Bonner (2002) calls Flexner "the severest critic and the best friend American medicine ever had."
In his 1930 Universities: American, English, German, Flexner, returning to his earlier interest in the direction and purpose of the American university, attacked distractions from serious learning such as intercollegiate athletics, student governments, and other student activities. "Intellectual inquiry, not job training, [is] the purpose of the university."
Flexner is buried in Cave Hill Cemetery in Louisville.