The building of the University of Pennsylvania was designed by Karp and Stevenson. The two architects combined the architectural styles of Oxford University and Cambridge University in England, while retaining some ancient elements of Gothic architecture, they innovatively developed a brand-new campus Gothic architectural style. The central campus of the school covers an area of 269 acres (about 1 square kilometer), extending to Philadelphia in the west and adjacent to Jueshuo University in the northeast, forming a campus with many departments and research institutes. The school has strengthened the planning of surrounding areas and opened new restaurants, large supermarkets and cinemas in the west of the campus.

In addition, the school has a 92-acre botanical garden in the southwest suburb of Philadelphia, which is also the official botanical garden in Pennsylvania. There is also a 687-acre large animal health center near Kennedy, west of Philadelphia, which belongs to the College of Veterinary Medicine of the University of Pennsylvania.