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Donohoe was born in London, the daughter of Joanna and Ted Donohoe, antique dealers. Her father (who also worked for the foreign office), is of Irish/Russian descent and her mother is Swiss. She left home at sixteen, in her early twenties she was accepted at the Central School of Speech and Drama and in the late 1980s she decided to move to Los Angeles to expand her career.
Donohoe first came to attention of the worldwide audience in 1986 when she was cast opposite Oliver Reed as Lucy Irvine in Nicolas Roeg's Castaway (where she appeared nude in some sequences of the movie). She followed this up with roles in two Ken Russell films The Lair of the White Worm, based on a Bram Stoker novel, and The Rainbow, based on a D. H. Lawrence novel. In 1981, Amanda appeared in the music video for the song, "Stand & Deliver" by Adam & the Ants.
In February 1991, she took part in the first lesbian kiss on American television when her character CJ Lamb on LA Law kissed Abbie Perkins played by Michelle Greene. In the Spring of 2001 she replaced Jerry Hall in playing the role of Mrs Robinson on the London stage. She has a brief guest appearance in an episode of Ally McBeal. Donohoe has constantly worked in film since, and has appeared in several television roles Murder City, Bad Girls and most notably two seasons of L.A. Law. In 2005 she starred in the title role of Hedda Gabler at the Royal Exchange Theatre, Manchester.
Channel 4 ranked her as number 38 in their list of the 50 Greatest British actresses.
Donohoe is a feminist, a socialist and an atheist. Donohoe admits to having experimented with drugs but never became addicted. She dated Adam Ant in the early 1980s and punched an obsessed fan who threatened Ant with a knife and she lived with film maker Nick Broomfield for three years. She has been open about being bisexual telling Diva magazine "My first sexual experiences were with women and if a woman comes into my life who is absolutely stunning and satisfies me emotionally, intellectually and sexually I'm not going to draw the line and say 'I can't because you're a woman'". She has been romantically linked to Sandra Bernhard and Jim Carrey.
In 1993 she ranked 16th in Celebrity Sleuths 25 Sexiest and in 1995 she ranked 16th in FHM's 100 Sexiest Women.
- Foreign Body as Susan Partridge - 1986
- Castaway as Lucy Irvine - 1987
- The Lair of the White Worm as Lady Sylvia Marsh - 1988
- The Substitute as Gayle Richardson - 1993
- A Womans Guide To Adultery as Jo Saxon - 1994
- The Madness of King George as Lady Pembroke - 1995
- Liar, Liar as Miranda - 1997
- Starship Troopers 3 as Admiral Enolo Phid - 2008
- L.A. Law as Cara Jean Lamb - 1990 - 1992
- Frasier as Catherine - 1994
- Ally McBeal as Marianne Holt - 1997
- Murder City as DI Susan Alembic - 2004 - 2006
- Bad Girls as Lou Stoke - 2006
- Batman Beyond as The Queen 1999-2001
- Cymbeline as Helen - 1984
- Great Expectations as Estella - 1984
- The Admirable Crichton as Lady Catherine - 1984
- Uncle Vanya as Yelena - 1996
- Miss Julie as Miss Julie - 1996
- The Graduate as Mrs Robinson - 2001
- Hedda Gabler as Hedda Gabler - 2001