In the early 1970s, Chiles enjoyed a successful modeling career. She made her big-screen debut in Together for Days in 1972, followed by 1973's The Way We Were, in which she played opposite Robert Redford and Barbra Streisand, as Carol Ann, the college sweetheart of Redford's character. She was then cast as Jordan Baker in 1974's The Great Gatsby, alongside Mia Farrow and, again, Robert Redford.

Chiles lost her youngest brother to non-Hodgkin's lymphoma in 1978, which contributed to her decision to take a three-year hiatus from acting just as her career seemed to be blossoming. Her film career never fully recovered, and she struggled to find roles of the caliber she had previously enjoyed, although film critic Pauline Kael gave her good notices for her performances in Alan Alda's Sweet Liberty (1986). Her portrayal of reporter Jennifer Mack in James L. Brooks' Broadcast News (1987) was also well received, as was her turn in George A. Romero's horror flick Creepshow 2 in 1987, as a hit and run driver. In 1989, she appeared uncredited in a short but effective cameo as the estranged mother of Ione Skye's character in Say Anything... (1989).

Chiles was born in Houston, the daughter of Marion Clay Chiles and Barbara Wayne Kirkland Chiles. Her father was the brother of oil tycoon and Texas Rangers owner Eddie Chiles. She had two brothers: Clay Kirkland Chiles (died 1979), and william Edmonds Chiles, President and CEO of Bristow Group, Inc, and was raised in Alice, Texas.

She has worked in television, playing J.R. Ewing's love interest Holly Harwood in the 1982–1983 season of Dallas and guest appearances in series such as Hart to Hart (as a psychotic split-personality model), In the Heat of the Night, Murder, She Wrote, and The Nanny (with another Bond girl Ivana Miličević). Later high points included the indie films Diary of a Hitman (1991) and Curdled (1996). In 2005, friend Quentin Tarantino, with whom she had previously worked on the set of Curdled, recruited her to appear in the two-episode finale of season five of CSI: Crime Scene Investigation, which he wrote and directed.

She has since appeared as a stuffy high school principal in the 1996 Disney film Wish Upon a Star, and as a frightened cruise Passenger in the critically panned Speed 2: Cruise Control in 1997. She made a cameo appearance in the international release of the 1997 Bond spoof Austin Powers: International Man of Mystery, though her scene was cut in the United States release.

In the spring of 2002, she taught a course in film acting at the University of Houston. Unlike some "Bond girls", Chiles has said that "being a Bond-girl is a fun way to be remembered" although she jokes that being asked to sigh "Oh, James" is annoying as "you can't live up to people's fantasies".

Chiles studied at the University of Texas at Austin and the former Finch College in New York City, where she was discovered by a Glamour Editor looking for a young woman to feature on the cover of the magazine's annual college issue. She landed the job and soon had contracts with Wilhelmina Models in New York and Elite Models in Paris. Later, she studied acting under Roy London. She dated Don Henley but the relationship ended, and in 2005, she married money manager Richard Gilder. They are both honorary co-chairs of Northfield Mount Hermon, a school in Massachusetts, and he donated money to the school, and they named the Chiles Theater after her.