In 1968 the Indiana University programs in Indianapolis were brought together into one administrative unit, Indiana University-Indianapolis (IUI). Maynard Hine, dean of the IU School of Dentistry, became the chancellor of IUI. Hine had joined the faculty of the School of Dentistry in 1944 and became the school's dean in 1945. In 1969 IUI and the Purdue University Indianapolis Regional Campus merged to form IUPUI, and Hine became the chancellor.

During his four years as chancellor, Hine faced many challenges. He had to oversee the merging of the two regional campuses into a single entity. This process, complicated by the faculty-centric IU culture vs. the top-down management style of Purdue, included combining academic departments from the two campuses and developing organizational entities and procedures for the operation of IUPUI. He had to convince the faculties and staffs of the two campuses that the merger could work. He had to persuade the Indianapolis political and civic leaders, many of whom wanted the city to have a state university that was separate from IU and Purdue, that IUPUI was in the best interests of Indianapolis. Finally, he had to sell IUPUI to the general public as a university that could meet their needs.

Hine stepped down in 1973 when he reached the mandatory retirement age for senior administrators in the IU system (which Hine referred to as "statutory senility.") His successor as chancellor was Glenn Irwin, the dean of the IU School of Medicine. Irwin, a 1944 graduate of the School of Medicine, joined the school's faculty in 1950 and became dean in 1965. A 1974 reorganization of the university's administration under President John Ryan gave Irwin the additional title of vice president of Indiana University. In this position Irwin had supervisory authority over the schools unique to IUPUI and the IU systemwide Schools of Business, Continuing Studies, Dentistry, Medicine, Nursing, Public and Environmental Affairs, and Social Work.

During his 13 years as chancellor, Irwin oversaw the continuing growth of IUPUI's academic programs. His major focus, however, was on the physical development of the campus. $229 million were spent to build several new classroom buildings, parking garages, and athletic facilities.

Irwin retired in 1986 and was succeeded by Gerald Bepko, dean of the IU School of Law-Indianapolis. Bepko, a former special agent with the Federal Bureau of Investigation, joined the law school's faculty in 1973. He became an associate dean in 1979 and dean in 1982. Like Irwin, Bepko was an IU vice president with supervisory authority over both campus and systemwide schools. In 1991 Bepko became chair of the University Operations Cabinet, which reviewed and revised IU's non-academic policies with the goal of controlling costs and increasing efficiencies.

As chancellor, Bepko worked to strengthen IUPUI's position within Indiana's higher education system and to make it a model urban university. He stressed the "research corridor" of IU-Bloomington, Purdue-West Lafayette, and IUPUI, where research in such fields as technology and the life sciences would aid in the economic development of Indiana and help slow the migration of the state's college graduates to other parts of the country. During Bepko's years as chancellor, several new undergraduate and graduate programs were added, and University College was created. It provided orientation, mentoring and tutoring programs, and learning communities to help first-year students stay in school.

Bepko originally planned to retire as chancellor at the end of June 2003, but his plans changed when IU president Myles Brand resigned at the end of 2002 to become president of the National Collegiate Athletic Association. The IU Board of Trustees appointed Bepko interim president of IU, a position he held until Adam Herbert became president on August 1, 2003.

When Bepko became IU's interim president, the trustees named William Plater, IUPUI's executive vice chancellor and dean of the faculties, acting chancellor for IUPUI. Plater served in the position until June 2003, when Charles Bantz, provost and senior vice president for academic affairs at Wayne State University in Detroit, became IUPUI's fourth chancellor. He is the first IUPUI chancellor who did not have previous ties to the university.

At the December 2003 ceremony marking his installation as chancellor, Bantz announced goals to double its efforts in several areas by 2010, including the number of bachelor degrees annually awarded, the amount of money for research that the campus receives, IUPUI's efforts at community partnerships, the number of students doing internships, the number of students in service learning, the transfer of research that will help Indiana's economy, and achievements in diversity. IUPUI has since received several awards related to community service and civic engagement.

In 2004 the Campaign for IUPUI, a comprehensive fundraising campaign launched under Gerald Bepko, ended after raising slightly over $1 billion, the first time that a campaign by a public university in Indiana had surpassed the $1 billion mark. It also made IUPUI one of only 22 universities in the United States up to that time that had completed campaigns that had reached that mark.

Bantz's role within the IU system changed in 2006 as part of an administrative reorganization sparked by faculty complaints at IU-Bloomington. Under the reorganization, the IU president has direct responsibility for the administration of the Bloomington campus. Bantz is the executive vice president of IU as well as chancellor of IUPUI. He oversees the academic and administrative affairs at IUPUI and the IU regional campuses.

Bantz retired as chancellor in 2015. He was succeeded by Nasser Paydar, who had previously served as a faculty member and executive associate dean in the School of Engineering and Technology, vice chancellor and dean at Indiana University-Purdue University Columbus, chancellor of Indiana University East, and Executive Vice Chancellor and Chief Academic Officer at IUPUI.