[14] Throughout the 1990s, she appeared in several Australian television shows, such as Wildside (1997) and Echo Point (1995), and starred as the love interest in the film Two Hands (1999), opposite fellow up-and-coming actor Heath Ledger.

"[5] On stage, Byrne starred in La Dispute and in a production of Anton Chekhov's classic Three Sisters at the Sydney Theatre Company.

In 2003, Byrne starred in three Australian films; The Night We Called It a Day, with Melanie Griffith and Dennis Hopper; The Rage in Placid Lake, with Ben Lee; and Take Away, alongside Vince Colosimo, Stephen Curry, John Howard and Nathan Phillips.

All films were comedies and opened to varying degrees of success at the box office, but The Rage in Placid Lake earned Byrne an AACTA Award nomination for Best Actress.

In the epic drama Troy (2004), she took on the role of Briseis, the captured priestess presented to "amuse" Brad Pitt's Achilles.

[17] Variety's review of the film stated: "Byrne's spoils-of-war chattel plays more as a convenient invention than as a woman who could possibly turn Achilles’ head and heart around".

[18] In her other 2004 film release, the thriller Wicker Park, Byrne appeared, opposite Josh Hartnett and Diane Kruger, as the girlfriend of a young advertising executive's old friend.

In 2006, Byrne portrayed Gabrielle de Polastron, duchesse de Polignac, a French aristocrat and friend of Marie Antoinette, in Sofia Coppola's Marie Antoinette, with Kirsten Dunst; and appeared as a medical examiner who thinks the dead woman she is prepping is her missing sister in the critically acclaimed thriller The Dead Girl,[21] directed by Karen Moncrieff.

[25] In 2007, Byrne began playing Ellen Parsons, a bright, young attorney, in the FX legal thriller television series Damages, alongside Glenn Close.

In her first 2011 release, James Wan's horror film Insidious,[31][32] she starred as a mother whose son inexplicably enters a comatose state and becomes a vessel for malevolent spirits in an astral realm.

[33] The comedy Bridesmaids featured Byrne as the rich, beautiful, elite wife of the groom's boss, alongside Kristen Wiig, Maya Rudolph, Melissa McCarthy, Ellie Kemper, and Wendi McLendon-Covey.

[34][35][36][37] Byrne appeared in X-Men: First Class, directed by Matthew Vaughn,[38] as Moira MacTaggert, a character she described as: "a woman in a man's world, she's very feisty and ambitious—you know, she's got a toughness about her which I liked".

[44] In The Place Beyond the Pines, a generational drama directed by Derek Cianfrance, she appeared with Ryan Gosling and Bradley Cooper, as the wife of a police officer who shoots a bank robber and has to deal with the consequences.

[45][46] She played a Google executive in the film The Internship, opposite Vince Vaughn and Owen Wilson, as she was drawn to "the way it addressed the generational gaps and the ever-changing landscape of the technological world".

[49] The film received mixed reviews from critics[50] and became the biggest opening day in North America box office history for the month of September following its release.

[52] 2014 saw Byrne star in the family dramedies Adult Beginners and This Is Where I Leave You as well as the comedy Neighbors, alongside Seth Rogen and Zac Efron, in which she played one half of a couple who come into conflict with a fraternity that has recently moved in next door.

[55][56] A critically panned but commercially successful remake of the 1982 classic, Annie, was released in December 2014 and featured Byrne playing the role of Grace Farrell, the titular character's mother figure and Mr.

In 2015, Byrne reunited with Melissa McCarthy and starred with Jude Law and Jason Statham in the hit comedic action film Spy,[57] playing the daughter of an arms dealer, and also starred with Susan Sarandon in the dramedy The Meddler as the daughter of an ageing widow who moves to Los Angeles in hopes of starting a new life after her husband passes away.

[58] In 2016, she reprised her roles in Neighbors 2: Sorority Rising and X-Men: Apocalypse,[59] and in 2017, she filmed the black comedy I Love You, Daddy, directed by and also starring Louis C.K., but it was dropped by its distributor following sexual misconduct accusations made against C.K.

[61] In Juliet, Naked (also 2018), a romantic comedy adapted from Nick Hornby's novel of the same name, she appeared as a woman dating an obscure rock musician (played by Ethan Hawke).

The film was an arthouse success, with Rotten Tomatoes' critical consensus reading: "Juliet, Naked's somewhat familiar narrative arc is elevated by standout work from a charming cast led by a well-matched Rose Byrne and Ethan Hawke.

Byrne also voiced a virtual assistant in the 2019 movie Jexi, costarring Adam Devine, Alexandra Shipp, and Wanda Sykes.

She was also featured in the "Most Beautiful People" list of 2007 in Who Magazine, and ranked 5th in Hallmark Channel's 2008 "TV's Sexiest Leading Woman" poll.

[...] Any doubts about Byrne's massive comedic talent—and after Bridesmaids and Neighbors, you'd have to be pretty stubborn to still have doubts—were put to rest with 2015's Spy, where she again steals the show as merciless terrorist Rayna.