Born and raised in New Haven, Connecticut, Scully attended Hillhouse High School. At the age of 16, he entered Yale University. He earned his BA degree from Yale in 1940, his M.A. in 1947, and his Ph.D in 1949. He has taught classes at Yale since 1947, often to packed lecture rooms. He is also a Distinguished Visiting Professor at the University of Miami. Scully officially retired from Yale in 1991, but continued giving courses there and at the University of Miami. He announced in 2009, however, at the age of 89, that he was no longer well enough to continue teaching.

Scully's early advocacy was critical to the emergence of both Louis I. Kahn and Robert Venturi as important 20th Century architects. Scully was a fierce critic of the 1963 destruction of New York's original Pennsylvania Station, memorably writing, "One entered the city like a god. One scuttles in now like a rat."

In 1952, Scully and his co-author Antoinette Downing won the Alice Davis Hitchcock Award for their book, The Architectural Heritage of Newport.

In 1995, the National Endowment for the Humanities chose Scully to deliver the Jefferson Lecture, the U.S. federal government's highest humanities honor. His lecture was on the topic of "The Architecture of Community," a concept that became central to his architectural philosophy.

In 1999, the Vincent Scully Prize was established by the National Building Museum to honor individuals who have exhibited exemplary practice, scholarship or criticism in architecture, historic preservation and urban design. Scully himself was the first honoree.

In 2003 the Urban Land Institute awarded Scully its J.C. Nichols Prize for Visionary Urban Development.

In 2004, President George W. Bush presented Scully with the National Medal of Arts, the United States' highest honor for artists and arts patrons. The medal citation read: "For his remarkable contributions to the history of design and modern architecture, including his influential teaching as an architectural historian."