On stage, she appeared in Sexual Perversity in Chicago and Fool for Love. Her movie appearances include Jerry Maguire, Trial and Error, Office Space and The Real Blonde. She has also made many appearances on television, including In Living Color and The Tonight Show with Jay Leno. In 1995, she played Jerry's girlfriend Sheila ("Schmoopie") in the famous "Soup Nazi" episode of Seinfeld. 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 on the Oprah Friday's Live in Chicago chat show as a semi-regular panelist.

On November 20, 2001, she married George Stephanopoulos, a well-known ABC News "Chief Washington Correspondent" and host of ABC's Sunday morning political affairs program, "This Week," and former political advisor to the Clinton administration. They have two daughters: Elliott Anastasia and Harper Andrea.