She has acted mainly on television, but she has also played various parts in films.
The eldest of three children, Stringfield was born in Colorado Springs, Colorado. Her family briefly relocated to Albuquerque, New Mexico, before settling in Spring, Texas, a suburb of Houston, where Stringfield grew up.
She developed a penchant for acting while attending Klein High School, where she starred in various musicals and plays including Oklahoma, Mother Courage, and Fiddler on the Roof. At 18 she attended the Acting Conservatory of SUNY at Purchase — rooming with fellow actress and student Parker Posey. During that time, she appeared in numerous off-Broadway productions and learned to control and alter her Texan accent with the help of a college speech teacher. Stringfield graduated in 1989 with a Bachelor's degree in Fine Arts.
She got her first role on the CBS Daytime soap opera Guiding Light, playing Christina "Blake" Thorpe from 1989 until 1992. After three years she left the show to spend a year traveling Europe, but soon returned to television on the ABC drama, NYPD Blue. She played Manhattan Assistant District Attorney Laura Kelly, the ex-wife of officer John Kelly (David Caruso) during the first season (1993–94) of the series. Unsatisfied, she was released early from her contract.
Stringfield became one of the original cast members of NBC's medical drama, ER. Her personal success mirrored the show's success — she was nominated for an Emmy Award for lead actress during each of her first three seasons of the show. Stringfield was contractually tied to appear in five seasons of ER; however, a desire for a "normal life" and to escape ER's grueling filming schedule prompted her to leave the drama early in its third season. In order to be released from her contract, Stringfield was forced to sign a no-work agreement, which blocked her from working on television for the remainder of her original contract. Stringfield's decision to quit reportedly angered the show's executive producer, John Wells, because she left just as Dr. Lewis got embroiled in a budding romance with Anthony Edwards' Dr. Mark Greene. Stringfield has commented: "I wouldn't describe the situation as pleasant. The producers were in shock. They tried to talk me out of it. It took a long time to get out of my contract."
Stringfield's much publicised departure reportedly "sent a small shock wave through Hollywood" and her exit episode in November 1996 attracted 37 million viewers, the biggest night of the season for the NBC network. Stringfield quit just as television executive Dick Robertson was closing a deal that guaranteed the ER cast millions in future earnings from sales to cable and syndication, meaning she effectively "walked away from a fortune."
Stringfield claims she was asked to reprise the role of Susan Lewis in ER several times, but turned each offer down. However, following the birth of her daughter, she approached the producers of ER and then rejoined the cast in 2001, the show's eighth season. "I changed my mind," Stringfield commented, "I really want to work now. It just made sense for me to go back to ER." 26.7 million people watched Stringfield's return, placing the show at first place in the ratings. During her second stint in ER, Stringfield's character was featured in a special 'crossover' with NBC's New York City based police drama, Third Watch, which aired in 2002. She remained in the role for four additional seasons, however in August 2005, Stringfield announced that she would be leaving the show again as the 12th season came underway. "I am extremely grateful for the time I spent on ER," Stringfield explained. "It is a wonderful show, and there are so many people I will miss. But I'm ready for new roles and new challenges." In 2009, Stringfield returned to ER for the series finale "And in the End...".
After leaving ER in 1996, Stringfield taught a script analysis class and directed several plays at her alma mater. She took roles in films such as 54 (1998) and Autumn in New York (2000) and appeared in the television movies Border Line (1999) — produced by her ER co-star Anthony Edwards — and Going Home (2000), in which she starred opposite Jason Robards. She also guest-starred in the CBS drama Touched by an Angel in 1999.
In 2005, Stringfield was cast alongside Michael Michele, Blair Underwood, Esai Morales, Gary Cole and Catherine Bell in the pilot episode of the CBS drama Company Town (created by Elwood Reid; directed by Thomas Carter), playing Angie Amberson, a mother of teenagers and a whistle-blower on the investment firm where she works. Company Town failed to get picked up for the 2006 fall season. The series was produced by Jack Clements and Larry Sanitsky. In 2007 Stringfield starred in the Andrew Shea film Forfeit. She played the role of Karen, the ex-girlfriend of a clinical sociopath who schemes and plots to stage a massive robbery and sets Karen up to take the rap.
In 2007, Stringfield guest-starred as attorney Nora March in the CBS drama Shark. She also played a recurring role in the HBO drama Tell Me You Love Me (previously known as Sexlife), which also aired in 2007. In 2009, she appeared in The Stepfather, a remake of the 1987 American thriller film of the same name.
She appeared in an episode of the USA Network drama In Plain Sight. Stringfield also guest-starred on Law & Order in late 2008 as a ruthless court clerk and Michael Cutter's love interest. She most recently played Mary Jane Porter, an old girlfriend of Larry David's who runs into and then goes on a date with him in an episode of Curb Your Enthusiasm that aired on October 11, 2009.
In 2010, Stringfield appeared in Who Is Clark Rockefeller? playing the role of Sandra Boss.
In addition to acting, Stringfield has done voice-over work, including the voice of Eyeleen in the children's television show Blue's Clues and voicing her ER character for the PC game ER: The Game. Stringfield was also featured in the U.S. Got Milk? advertising campaign, despite being lactose intolerant.
In 2012, Stringfield starred in The Confession, a Hallmark Channel movie and a sequel to The Shunning.
In November 2013, Stringfield guest-starred in the CBS police drama CSI: Crime Scene Investigation in season 14: episode 8 titled "Helpless", playing swing shift CSI Dawn Banks. In 2014, Stringfield played a recurring role on the CBS mystery Under the Dome during its second season.
Recently(2017), Stringfield has appeared on Criminal Minds spinoff, Criminal Minds: Beyond Borders as the wife of Gary Sinise's character, Jack Garrett.
In 1991 and 1993, Stringfield was nominated in the "Outstanding Villain/Villainess" category at the Soap Opera Digest Awards for her role in Guiding Light. She has also received multiple awards and award-nominations for her role as Susan Lewis in ER, including three separate Emmy Award nominations in the category "Outstanding Lead Actress in a Drama Series" in 1995, 1996 and 1997. In 1995 she was nominated in the category "Favorite Female Performer" at the People's Choice Awards and in 1995 and 1996 she was nominated in the "Best Performance by an Actress in a TV-Series -Drama" category at the Golden Globe Awards.
In 1996, she won a Q Award for "Best Actress in a Quality Drama Series" and in 1997 she, along with several of her ER cast-mates, won a Screen Actors Guild Award for "Outstanding Performance by an Ensemble in a Drama Series". In addition Stringfield was voted one of the "100 Sexiest Women in the World" by readers of FHM Magazine in 1997.
In the early 1990s Stringfield dated British businessman Paul Goldstein (chairman of Nevica skiwear) for nearly three years, but the pressures of a long-distance romance eventually ended the relationship.
Stringfield married journalist Larry E. Joseph in October 1998. They have two children: their daughter, Phoebe (born March 2001) and son Milo (born April 2004). Stringfield and Joseph divorced in January 2006 after seven years of marriage. She currently resides in Los Angeles.