[3] She grew up in Melbourne, just around the corner from the Como Centre—a multi-storey office, retail cinema and hotel complex, featuring the headquarters of Channel 10 Television—on Chapel Street, where her mother ran a shop.

Her first credited screen role was that of an eleven-year-old girl from the Australian bush sent to live with her grandmother, on the ABC TV children's television series Sugar and Spice, which was broadcast between 1988 and 1989.

After obtaining a ten-episode arc as a parachute instructor in Neighbours in 1994, Mitchell returned to play the regular role of Catherine O'Brien, a strong-minded and opinionated student, from 1996 to 1997.

She found the experience of acting in a studio film "physically challenging", but was eager to take on the role, explaining: "Well, it's an interesting script, great character, shot in Australia, get to go home, you know, a whole range of reasons.

In 2000, she also starred as an expecting mother in the psychological drama Everything Put Together, which was nominated for the Grand Jury Prize at the Sundance Film Festival, and as the love interest of a lawyer in the romantic comedy Cowboys and Angels.

Joel Schumacher's thriller Phone Booth (2003), opposite Colin Farrell, featured her as the wife of a young arrogant publicist who becomes a victim of a mysterious caller who threatens to harm him.

Her three 2004 film releases —Man on Fire (2004), with Denzel Washington, the Academy Award–winning Finding Neverland, with Johnny Depp and Kate Winslet, and Woody Allen's Melinda and Melinda— were well received by critics and successful at the box office.

In its review for the film, Variety noted: "Mitchell socks over her role as a dynamo whose emotional insecurity is buried under a fabulously attractive exterior; by virtue of her character's assertiveness, she dominates the screen".

James Berardinelli noted: "Radha Mitchell normally does smaller movies, but her experience from Pitch Black serves her well here; she's credible as a mother who will fight off hoards of dead to save her daughter".

In 2007, Mitchell starred in Robert Benton's romantic dramedy Feast of Love, opposite Greg Kinnear and Morgan Freeman, as a successful realtor carrying on an affair with a married man,[24][25] and in the horror film Rogue, with Michael Vartan, as a wildlife researcher fighting a giant, man-eating crocodile.

[28] The horror film The Crazies (2010) featured Mitchell as a pregnant woman and one of the residents of a fictional Iowa town that becomes afflicted by a military virus that turns those infected into violent killers.

[31] Mitchell reprised her role of Rose Da Silva in Silent Hill: Revelation (2012), which was a moderate box office success, grossing over US$56 million worldwide, but was heavily panned by critics and audiences,[32] Her next seven screen projects —the films Big Sur, Olympus Has Fallen, Evidence, The Frozen Ground, Standing Up, Expecting and the ABC drama series Red Widow— were released throughout 2013.

(2014), a comedy written by and starring John Leguizamo, Mitchell played a neurotic uptown girl and the love interest of an unattractive man rejected by women because of his donkey-faced appearance.

In Looking for Grace (2015), a drama screened in the main competition section of the 72nd Venice International Film Festival,[36][37] Mitchell starred as a mother hiring a private detective in an attempt to find her missing daughter.