The University is located eight miles (13 km) south of the Loop in the Chicago neighborhoods of Hyde Park and Woodlawn. The campus is noted for its Gothic architecture (carried out entirely in limestone); the buildings and layout of the Main Quadrangle have been deliberately patterned after Cambridge from the founding of the University. More contemporary buildings have attempted to complement the style of the original buildings with mixed success. One of the most striking buildings is the brutalist Regenstein Library. The campus is home to several significant buildings, including Rockefeller Memorial Chapel (notable for its solid stone construction) and Frank Lloyd Wright's Robie House. The campus spans the Midway, a large linear public park which was a part of the 1893 World's Columbian Exposition. The bulk of the campus, including the main quadrangle and the hospitals, are north of the Midway; several of the professional schools are located south of the Midway.

A $2 billion capital campaign (as of 2004 over half way completed) has brought unprecedented expansion to the school. The last few years have featured much change on campus: the unveiling of Max Palevsky dormitory (primarily for first year students), the conversion of Bartlett Gym into a dining hall, the opening of the new Ratner Athletic Center (a Cesar Pelli design) and matching parking/office structure, the construction of the new Comer Children's Hospital, the Graduate School of Business' new Hyde Park Center (a Santiago Calatrava building), and an Interdivisional Research Building for sciences (still under construction). The University has also expanded outside of Hyde Park, opening the new Gleacher Center (a Business School center) in the Chicago Loop, international Business School centers in Barcelona (moving soon to London) and Singapore, and the new Paris Center on the left bank (for collegiate study abroad). The University plans to direct the next stage of its “master plan” towards revamping and consolidating dormitories, many of which are far from campus and aging poorly. Plans are being prepared for the construction of a new undergraduate dormitory on land south of the Midway.