Most of the campus occupies the eastern half of the mouth of Mānoa Valley on Oahu, with the John A. Burns School of Medicine located adjacent to Kakaʻako Waterfront Park.

It is accredited by the WASC Senior College and University Commission and governed by the Hawaii State Legislature and a semi-autonomous board of regents.

[11] The bill Maui Senator William J. Huelani Coelho through the initiatives of Native Hawaiian legislators, a newspaper editor, petition of an Asian American bank cashier, and a president of Cornell University,[12] was introduced into the Territorial Legislature March 1, 1907 as Act 24, and signed into law March 25, 1907 by Governor George Carter, which officially established the College of Agriculture and Mechanic Arts of the Territory of Hawaiʻi under a five-member Board of Regents[12] on the corner of Beretania and Victoria streets (now the location of the Honolulu Museum of Art School).

[12] With classes scheduled to start in February 1908, the regents persuaded Willis T. Pope, vice principal of the Territorial Normal School, to head the college for its first semester.

In Spring 1908, the regents appointed John W. Gilmore, professor of agriculture at Cornell University, as the college's first president.

[12] It officially became an institution of higher learning on September 14, 1908, when it enrolled 5 freshmen registered for a bachelor of science degree.

Willis T. Pope went on to become the Superintendent of Public Instruction in the Territory of Hawai’i from 1910 until 1913 and later a professor of botany and horticulture at the university.

[11] William Kwai Fong Yap, a cashier at Bank of Hawaii, and a group of citizens petitioned the Hawaii Territorial Legislature six years later for university status which led to another renaming finally to the University of Hawaiʻi on April 30, 1919, with the addition of the College of Arts and Sciences and College of Applied Science.

Following the attack on Pearl Harbor in December 1941, classes were suspended for two months while the Corps of Engineers occupied much of the campus, including the Teacher's College, for various purposes.

The university's ROTC program was put into active duty, which made the campus resemble a military school.

When classes resumed on February 11, 1942, about half of the student and faculty body left to enter the war or military service.

Enrollment continued to grow to 19,000 at the university through the 1960s and the campus became nationally recognized in research and graduate education.

The board also appoints the president of the University of Hawaiʻi System, who provides leadership for all 10 campuses, including as the chief executive of UH Mānoa.

Since that initial period, the University of Hawaiʻi at Mānoa has always been led by a president, chancellor, or provost, including interim or acting roles.

[16] In 1974, the role of chancellor was established to handle campus-specific leadership, allowing the UH President to focus on system-wide governance.

[14] In 2001, the position of chancellor was re-established by UH System president Evan Dobelle over conflict of interest concerns.

[21] As the school outgrew its location on the Punchbowl side of Honolulu, a new campus was to be constructed on the corner of University Avenue and Metcalf Street.

[23] The College of Business Administration was established in 1949 with programs in accounting, finance, real estate, industrial relations, and marketing.

The National Science Foundation ranked UH Mānoa 45th among 395 public universities for Research and Development (R&D) expenditures in fiscal year 2014.

[39] The university offers over 50 distance learning courses, using technology to replace either all or a portion of class instruction.

[40] With extramural grants and contracts of $436 million in 2012, research at UH Mānoa relates to Hawaii's physical landscape, its people and their heritage.

The geography facilitates advances in marine biology, oceanography, underwater robotic technology, astronomy, geology and geophysics, agriculture, aquaculture and tropical medicine.

Its heritage, the people and its close ties to the Asian and Pacific region create a favorable environment for study and research in the arts, genetics, intercultural relations, linguistics, religion and philosophy.

[41][42] For the period of July 1, 2012 to June 20, 2013, the School of Ocean and Earth Science and Technology (SOEST) received the largest amount of extramural funding among the Mānoa units at $92 million.

In 1922, the relationship was formalized and it was one of the largest and most active groups on the university's campus, including hosting events for high school and incoming students.

[52][51] In 1932, through funding by the Atherton family, the YMCA moved across the street to a three-story cement building on University Avenue.

In 1995, the YMCA purchased the Mary Atherton House next door to provide additional residential and activity space.