[10] During her senior year of college, Close became inspired to pursue a career in acting after watching an interview of Katharine Hepburn on The Dick Cavett Show.

During her years at school in Williamsburg, she also starred in the summer-time outdoor drama, The Common Glory, written by Pulitzer Prize author Paul Green.

[13] In her senior year of college, she called her school's theater department to be nominated for a series of auditions through the University Resident Theatre Association and TCG.

[17] From September 1978 to April 1979, Glenn appeared on Broadway in The Crucifer of Blood playing the part of Irene St. Claire, with Paxton Whitehead and Dwight Schultz.

Her last major stage role before beginning her motion picture career was playing Chairy, the female lead in the Broadway musical Barnum, from April 1980 to March 1981.

"[21] Close also starred opposite Robert Duvall in the drama The Stone Boy (1984), a film about a family coping after their youngest child accidentally kills his older brother in a hunting accident.

Close was given favorable reviews and even received her second Golden Globe Award nomination, but the movie was critically panned and under-performed at the box office.

The film propelled Close to international stardom and the character of Alex Forrest is considered one of her most iconic roles; the phrase "bunny boiler" has even been added to the dictionary, referring to a scene from the movie.

[28] Also in 1988, she appeared alongside Keith Carradine in Stones for Ibarra, a television film adapted from the book written by Harriet Doerr and produced by the Hallmark company.

[31] She also portrayed the title subject of the fact-based made-for-TV movie Serving in Silence: The Margarethe Cammermeyer Story in 1995, for which she won her first Primetime Emmy Award.

[37] Close appeared in the newsroom comedy-drama The Paper (1994), directed by her good friend Ron Howard and in 1996 she acted alongside the cast of Tim Burton's alien invasion satire Mars Attacks!

Her role as Cruella de Vil was universally praised and earned her a nomination for Golden Globe Award for Best Actress – Motion Picture Comedy or Musical.

She had been working on the project, in which she appeared alongside 101 Dalmatians co-star Mark Williams, for almost twenty years, and aside from starring in it, she co-wrote the script and produced the film.

[50] Close stated it became more important for her to make the film in order to stimulate discussion on transgender issues, commenting, "There came a point where I asked, 'Am I willing to live the rest of my life having given up on this?'

"[51] In the film, Close played the title role of Albert Nobbs, a woman living as a man in 19th century Ireland after being sexually assaulted as a young girl.

When asked during the film's awards campaign about the fact of not having an Oscar, Close said: "I remember being astounded that I met some people who were really kind of almost hyper-ventilating as to whether they were going to win or not, and I have never understood that.

In October 2014, Close returned to Broadway in the starring role of Agnes in Pam MacKinnon's revival of Edward Albee's A Delicate Balance at the John Golden Theatre.

[58] In 2016, she appeared in The Great Gilly Hopkins and starred in the British zombie horror drama The Girl with All the Gifts (2016) as Dr. Caldwell, a scientist researching a cure to save humanity.

[77][78] An adaptation of Meg Wolitzer's novel of the same name, the film stars Close as Joan Castleman, who questions her life choices as she travels with her husband to Stockholm, where he is set to receive the Nobel Prize in Literature.

Also in 2018, Close made a return to the stage, where, from September to December, she featured in the Off-Broadway play, Mother of the Maid, at the Public Theater in New York City.

[91] In 2021, Close served as an executive producer alongside Emma Stone for Cruella, a Disney live-action spin-off/prequel of One Hundred and One Dalmatians, directed by Craig Gillespie.

[104] Other cast members for the film include Daniel Craig, Jeremy Renner, Andrew Scott, Cailee Spaeny, Josh O'Connor, and Kerry Washington.

[107][108][109] In May 2024, it was announced that Close was reuniting with her Reversal of Fortune costar Jeremy Irons in the upcoming Simon Curtis-directed retirement home comedy Encores, with Henry Winkler and Don Johnson also co-starring.

[120] "Glenn is often described as having a glacial or distant quality about her, but in person she's the absolute opposite: warm and intimate," says actor Iain Glen, who co-starred with her in the 2002 stage production of A Streetcar Named Desire.

"[124] Film historian Cari Beauchamp has stated, "When you look at the top 10 actresses of the past 80 years, since sound came in, first you have Bette Davis, Katharine Hepburn and Meryl Streep – but I think Glenn Close is definitely in that list.

She also helped dedicate William & Mary's newly renovated Phi Beta Kappa Memorial Hall, whose main stage theater was named the Glenn Close Theatre in her honor.

[149] Her political donations have mostly been made in support of Democratic politicians, including Hillary Clinton, Howard Dean, John Edwards, Angus King, and Barack Obama.

[169][170] Close is also a trustee of The Wildlife Conservation Society[171] and volunteers at Fountain House in New York City, a facility dedicated to the recovery of those suffering from mental illness.

[176] Close was a founder and is chairperson of Bring Change to Mind,[177] a US campaign to eradicate the stigma and discrimination surrounding mental illness, supporting her sister Jessie who has bipolar disorder.

[183] On June 16, 2016, Close donated $75,000 to the Mental-Health Association of Central Florida in order to fund counseling and other assistance to victims of the Orlando nightclub shooting.