Wentworth was born in Washington, D.C. She is the daughter of Mabel Cabot, who was First Lady Nancy Reagan's social secretary in the White House, and Eric Wentworth, a reporter for The Washington Post. She is also a granddaughter of the explorer Janet Elliott Wulsin (1894–1963). She attended the Dana Hall School for Girls in Wellesley, Massachusetts, and graduated from Bard College, in Annandale-on-Hudson, New York.

Wentworth appeared onstage in Sexual Perversity in Chicago and Fool for Love. Her movie appearances include Jerry Maguire, Trial and Errorand The Real Blonde. She has also made many appearances on television, including being a cast member on In Living Color and appearances on The Tonight Show with Jay Leno. In 1995, she played Jerry's girlfriend Sheila ("Schmoopie") in the famous "Soup Nazi" episode of Seinfeld. In 1997, she appeared as the love interest in the television film The Love Bug.

In 2003, she co-hosted the syndicated talk show Living It Up! With Ali & Jack, with Jack Ford.

She authored The WASP Cookbook, ISBN 978-0446912105.

Wentworth is currently starring in the comedy Head Case, on the Starz TV network. She frequently appears on The Oprah Winfrey Show as a correspondent and on the Fridays Live segments in Chicago as a semi-regular/regular panelist.

On November 20, 2001, she married George Stephanopoulos, ABC News host of ABC's morning program, Good Morning America, and former political adviser to the Clinton administration. They have two daughters: Elliott Anastasia and Harper Andrea.