Heche began her professional acting career on the NBC soap opera Another World (1987–1991), earning a Daytime Emmy Award for her portrayal of twins Vicky Hudson and Marley Love.

[40] Heche attended the progressive Francis W. Parker School, where she continued to be active in theater, performing in such plays as Thornton Wilder's The Skin of Our Teeth and Irwin Shaw's Bury the Dead.

However, right after applying to design school, she was offered a small supporting role in the Hallmark Hall of Fame television film adaptation of the Willa Cather novel O Pioneers!, featuring Jessica Lange.

[53] Heche also starred in several roles in Los Angeles theater productions in 1991 and 1992, including "Us & Them", a Generation X slice-of-life piece,[52][54] and Getting Away With Murder, a stage adaptation of the James M. Cain stories Dead Man and The Baby in the Icebox, which were produced as part of the Mark Taper Forum–sponsored "Sundays at the Itchey Foot" series.

Over the next two years, she performed mainly bit parts in feature films such as A Simple Twist of Fate (1994) and larger supporting roles in cable television movies such as Girls in Prison (1994) and Kingfish: A Story of Huey P. Long (1995).

Heche appeared in her first lead role (albeit receiving third billing) in Donald Cammell's straight-to-video erotic thriller Wild Side (1995), alongside Christopher Walken and Joan Chen.

[58][59] In 1996, Heche had the starring role as a college student contemplating an abortion in a segment of the HBO anthology film If These Walls Could Talk, co-starring Jada Pinkett Smith and Cher.

[62] In 1997, Heche starred in what has been described as her breakthrough role in the hit crime drama Donnie Brasco as the wife of the main character, an FBI undercover agent played by Johnny Depp.

[63] By the late 1990s, Heche continued to find recognition and commercial success as she took on supporting roles in three other 1997 high-profile film releases—Volcano, I Know What You Did Last Summer and Wag the Dog.

[64] Heche portrayed the minor role of a backwoods loner in the slasher thriller sleeper hit I Know What You Did Last Summer, starring Jennifer Love Hewitt, Sarah Michelle Gellar, Ryan Phillippe, and Freddie Prinze Jr.

[66] She obtained the part of a presidential advisor opposite Robert De Niro and Dustin Hoffman in the political satire Wag the Dog, a role that was originally written for a man.

[70] Although she was cast in a second starring role shortly thereafter as Vince Vaughn's love interest in the drama Return to Paradise (1998), Heche felt that her relationship with DeGeneres destroyed her prospects as a leading woman.

[75] In an otherwise negative Times review of the film, Janet Maslin felt that Heche was "refreshingly cast in Marion's role", while noting that her portrayal was "almost as demure as Ms. Leigh's, yet she's also more headstrong and flirty.

[90] In 2002, Heche made her Broadway debut in a production of the Pulitzer Prize-winning drama Proof, in the role of a young woman who has inherited her father's mathematical genius and mental illness.

During the airing of the show, Heche starred in the romantic comedy What Love Is (2007)[95] and in Toxic Skies (2008), a science-fiction thriller based on the chemtrails conspiracy theory.

[98] Matthew Turney of View London felt that "[t]here's also terrific support" from Heche in what he described as an "enjoyable, sharply written and beautifully shot LA drama".

[99] Also in 2009, she was cast in the HBO dramedy series Hung, in a supporting role as the ex-wife of a financially struggling high school coach-turned-male prostitute, portrayed by Thomas Jane.

[101][102] David Rooney of The Hollywood Reporter remarked in his review for the film, "while Heche shines brightest in more brittle mode, as in HBO's Hung, she strikes a sweet balance between Joan's mischievous and maternal sides".

[108] Heche starred with James Tupper, Jennifer Stone, and Rebekah Brandes in the supernatural horror film Nothing Left to Fear (2013), about a family's life in a new town being interrupted by an unstable man of the cloth.

[114] USA Network's action-adventure drama series, Dig, had Heche portray the head of the FBI field office in Jerusalem whose agents uncover a 2,000-year-old conspiracy while investigating an archaeologist's murder.

Heche played Karen Copeland, a United States Air Force pilot who must navigate Armageddon, with her university-professor husband Josh (James Tupper) and their three nearly adult children.

[119][120] In another independent film, the comedy Catfight (2016), Heche starred opposite Sandra Oh, portraying one of two bitter rivals who pursue a grudge match that spans a lifetime.

[126] On September 25, 2017, Heche debuted as the series lead playing DIA Deputy Director Patricia Campbell in the military/espionage thriller The Brave, which lasted for one season on NBC.

[129][130] The following year, she co-starred in an ensemble cast in Lindsay Gossling's 13 Minutes about four families struggling with multiple dilemmas in a fictional Oklahoma town just before a devastating tornado hits.

In 2001, Heche published a memoir titled Call Me Crazy,[134] which discussed her family and career background, as well as disclosed her history of mental illness and alleged childhood sexual abuse by her father.

Bergman was a university lecturer in literature and a Christian writer, whose 1994 memoir titled Anonymity described their closeted gay father and the effects that his legacy had on the rest of the family.

[189][190] Heche left her vehicle at the side of a rural road and, wearing only a bra and shorts, walked 1.5 miles (2.4 km) in extremely hot weather without water, before feeling dehydrated and knocking on the door of a ranch house.

[201] The Los Angeles Police Department said that a preliminary blood analysis showed the presence of both cocaine and narcotics, including fentanyl, in her system; however, the coroner's report concluded that she was not impaired at the time of the crash.

[2][6][227][228] On December 6, 2022, the Los Angeles County Department of Medical Examiner-Coroner announced the results of Heche's autopsy, stating that she was not impaired by illicit substances at the time of the incident and that no active drugs were found in her system.

An inactive metabolite of cocaine was found through a blood test taken when Heche arrived at the hospital, which the coroner's office said indicates the drug was used in the past, but not at the time of the crash.