Sedgwick made her debut at the age of 16 on the television soap opera Another World as Julia Shearer, troubled granddaughter of Liz Matthews. In 1988, she made a strong impression in a TV version of Lanford Wilson’s Lemon Sky. During the 1990s, she appeared in several Hollywood movies, including Singles (1992), Heart and Souls (1993), Something to Talk About (1995), and Phenomenon, in which she played the love interest of John Travolta’s character. She starred in the Emmy Award–winning 1992 made-for-TV film Miss Rose White as a Jewish immigrant who comes to terms with her ethnicity. She played the parts of Mae Coleman in 2003’s Secondhand Lions and Stella Peck in the 2007 film The Game Plan. She also starred alongside her husband Kevin Bacon in the 2004 film The Woodsman. She dubbed the voice of Batwoman in the animated movie Batman: Mystery of the Batwoman.

Sedgwick married actor Kevin Bacon on September 4, 1988. Sedgwick learned in 2012, via her appearance on the U.S. TV show Finding Your Roots with Henry Louis Gates, that she and Bacon are tenth cousins, once removed.

Sedgwick starred in the television series The Closer from 2005 to 2012. In 2007, she began earning roughly US$300,000 per episode. Over the life of the series, she was nominated for and won several awards for her starring role as Deputy Chief Brenda Leigh Johnson. She received a Golden Globe award in 2007 for her performance as lead actress and won a Primetime Emmy Award in 2010. In 2009, Sedgwick was awarded a star on the Hollywood Walk of Fame for Television.

The Closer ended on August 13, 2012, following the completion of its seventh season; the series’s broadcaster, TNT, said that the decision to retire the series was made by Sedgwick. A sequel series starring most of the same cast called Major Crimes continued in its place.

Sedgwick produced the television series Proof for TNT which debuted in 2015 for one season. She is also featured in the NBC comedy series Brooklyn Nine-Nine portraying the character of Madeline Wuntch.

Sedgwick will play in the lead role of Jean Raines in the ABC comedy pilot My Village, written by Kari Lizer, The series was green-lighted by ABC and re-titled Call Your Mother on May 21, 2020 for the 2020-2021 television season.