Richardson has enjoyed a successful and extensive theatre career, first joining Manchester Library Theatre in 1979 as an assistant stage manager, followed by a number of appearances in repertory theatre. Her London stage debut was in Moving at the Queen's Theatre in 1981. She found recognition in the West End for a series of stage performances, ultimately receiving an Olivier Award nomination for her performance in A Lie of the Mind, and, in 1996, one critic asserted that she is "the greatest Actress of our time in any medium" after she appeared in Orlando at the Edinburgh Festival. She returned to the London stage in May 2009 to play the lead role in Wallace Shawn's new play, Grasses of a Thousand Colours at the Royal Court Theatre. Richardson has said that she prefers new work rather than the classics because of the history which goes with them.

Richardson began her career on stage and made her West End debut in the 1981 play Moving. She received a Best Actress Olivier Award nomination for the 1987 Royal Court production of A Lie of the Mind. On television, she starred in Blackadder (1986–1989), A Dance to the Music of Time (1997), Merlin (1998), The Lost Prince (2003), Gideon's Daughter (2006), the sitcom The Life and Times of Vivienne Vyle (2007), and Rubicon (2010).

In 1985, Richardson made her film debut as Ruth Ellis, the last woman to be hanged in the United Kingdom, in the biographical drama Dance with a Stranger. Around the same time, Richardson played a comedic Queen Elizabeth I, aka Queenie, in the British television comedy Blackadder II.

Following Dance with a Stranger, Richardson turned down numerous parts in which her character was unstable or disreputable, including the Glenn Close role in Fatal Attraction. In this period, she appeared in Empire of the Sun (1987). In an episode of the TV series The Storyteller ("The Three Ravens", 1988), she played a witch. Meanwhile, she had returned in guest roles in one episode each in Blackadder the Third (1987) and Blackadder Goes Forth (1989). She returned to play Queenie in the Christmas special Blackadder's Christmas Carol (1988) and, later, a special edition for the millennium Blackadder: Back and Forth.

Her portrayal of a troubled theatre goer in Secret Friends (BBC 2, 1990) was described as "a miniature tour de force... Miranda Richardson's finest hour, all in ten minutes" (The Sunday Times). Other television roles include Pamela Flitton in A Dance to the Music of Time (1997), Miss Gilchrist in St. Ives (1998), Bettina the interior decorator in Absolutely Fabulous, Queen Elspeth, Snow White's stepmother, in Snow White: The Fairest of Them All (2001), and Queen Mary in The Lost Prince (2003).

Her film credits also include Kansas City (1996), The Apostle (1997) and Wah-Wah (2005). In 2002, she performed a triple-role in the thriller Spider.

Richardson also appeared as Queen Rosalind of Denmark in The Prince and Me and as the ballet mistress Madame Giry in the film version of the Andrew Lloyd Webber musical The Phantom Of The Opera (2004). In 2005, she appeared in the role of Rita Skeeter, the toxic Daily Prophet Journalist in Harry Potter and the Goblet of Fire. She also did the voice for Corky in The Adventures of Bottle Top Bill and His Best Friend Corky (2005), an Australian animated series for children. In 2006, she appeared in Gideon's Daughter. She played Mrs. Claus in the film Fred Claus (2007).

In 2008, Richardson was cast in a leading role in original AMC pilot, Rubicon. She plays Katherine Rhumor, a New York socialite who finds herself drawn into the central intrigue of a think tank after the death of her husband.

Richardson was cast as Queen Ulla in Maleficent, where she was to play the titular character's aunt, but her role was cut from the film during post-production. In 2015, she played Sybil Birling in Helen Edmundson's BBC One adaptation of J. B. Priestley's An Inspector Calls.