Rancic was born in Naples, Italy and moved to the United States at the age of 5, where she was raised in the Washington D.C. metropolitan area. She is a graduate of Walt Whitman High School (Bethesda, Maryland), received a bachelor's degree in Journalism from the University of Maryland, College Park, and a master's degree in Journalism from American University. While in attendance, Rancic served as a features correspondent for the syndicated university television station, covering a number of stories related to the Pentagon, Supreme Court, White House and State Department.
Her father, Eduardo DePandi, is a master tailor. The DePandi family owns Bruno Cipriani, a high-end men's clothing store in the White Flint Mall in North Bethesda, Maryland. She has two siblings: a sister, Monica, and an opera singer brother, Pasquale DePandi.