Indiana University (IU) established its first extension center at Indianapolis in 1916, although the first IU course was taught in Indianapolis in 1890. The Indianapolis campus of Purdue University (PU) grew out of World War II training programs sponsored by Purdue, and began its major operations in 1946. Indiana University established the Indianapolis regional campus in the mid-1960s. In 1968, the Trustees of Indiana University created Indiana University at Indianapolis, and less than a year later, in 1969, the trustees of Indiana and Purdue universities merged their Indianapolis operations to form Indiana University–Purdue University at Indianapolis (IUPUI). Indiana University was selected to administer the campus. Purdue brought to the merger a growing complex of degree programs and Purdue’s traditional strengths in the physical sciences, engineering, and technology. The name of the campus was changed to Indiana University–Purdue University Indianapolis in 1992. As of 2009, IUPUI enrolled more than 28,000 students.

A restructuring of undergraduate programs at IUPUI in the Fall of 1972 created three new schools: the School of Liberal Arts (humanities and the social sciences), the School of Engineering and Technology, and the School of Science (physical, behavioral, and life sciences).

After being housed for almost 22 years on the 38th Street campus, the School of Science made a historic move in two phases into two buildings on the main campus during 1991-1993.