After moving to the United States, George made her feature-film debut with a supporting role in the tech-noir, science-fiction film Dark City (1998).

She won the Logie Award for Most Outstanding Actress for her role in the Australian miniseries The Slap (2011), which she reprised in the 2015 American adaptation.

At the age of 16, George and a friend, Cara Mitchinson, both acted in a mock episode of the popular Australian soap Home and Away with a video camera, playing Bobby and Sophie Simpson; respectively.

When the offer of a role on the serial came, George's parents convinced her to relocate from her native Perth to Sydney and she began lodging with families.

While playing the role, George made property investments and wrote advice columns for two English teen magazines.

[7] She then made a health and fitness video, Mind, Body and Soul (1996), created a sleepwear line called "An Angel at My Bedside", and had a recurring role on the short-lived 1997 Fox Broadcasting Company television fantasy drama series Roar, which was filmed in Queensland, opposite Heath Ledger.

[8] A show about "the adventures of an intrepid pair of friends from Ohio who take their love for the macabre and use it to solve crimes plaguing Los Angeles",[9] she was to star alongside Bodhi Elfman and Fab Filippo.

[20] To explain her character's accent (George is Australian), the writers wrote that she was born in the United States but grew up in London.

[21] George left the show at the end of the third season, saying that "I got offered a couple of films so I decided to kind've [sic] move on.

[25] Despite unfavorable reviews, Film Threat praised George and her co-star Ryan Reynolds's performances, stating that they "make a striking couple.

However, the show underwent significant changes; with George and other castmates being replaced and with executive producers DeAnn Heline and Eileen Heisler, and writers Rand Ravich and Jill Gordon and director Nigel Cole all being fired.

[8][28][29] Also in 2006, she travelled to Brazil to film the horror-thriller Turistas (released in the UK and Ireland as Paradise Lost) with Josh Duhamel and Olivia Wilde.

[15] Shooting lasted three months on what was the first Hollywood film to be shot entirely on-location in Brazil, and George - who learned to speak Spanish and Portuguese for the role - said that the experience "made me a better actress; more resilient, tougher.

"[6][30] In 2007, she landed the lead role, Christine, in the biographical drama Music Within, opposite Ron Livingston, which focused on a disability-rights activist in Portland, Oregon.

"[32] She starred in the British horror-thriller WΔZ, and had a prominent role in the film adaptation of 30 Days of Night, directed by David Slade and co-starring Josh Hartnett.

[33] George returned to television in 2008 in the HBO half-hour drama In Treatment, co-starring Gabriel Byrne and Dianne Wiest, receiving a 2009 Golden Globe Award nomination for Best Supporting Actress – Series, Miniseries, or Television Film,[34][35][36] and also received a nomination for "Best Actress" at the 2009 Australian Film Institute Awards.

[37] In September 2008, George joined the cast of Grey's Anatomy for eleven episodes as Sadie Harris, a bisexual intern,[38] but in January 2009, it was released that she was leaving the show in a mutual agreement with the producers.

[42][43][44] George also received the lead role in the Australian-British mystery thriller by Chris Smith titled Triangle,[45] which opened to positive reviews.

A review of the U.S. series in The New York Times noted George's performance as "particularly beguiling ... As Rosie she is absurd, infuriating, sad, and very funny.

[55] George is credited as the inventor of Style Snaps, a device intended to allow changing pant hem length without sewing.

[61] In light of a publicised domestic-violence dispute between George and her boyfriend Jean-David Blanc in 2016, journalist Christine Sams, who had originally published the Sun-Herald article, wrote a public apology, in which she noted: "Many of those people attacking George have directly used those inane comments from my original interview (published years ago) to somehow justify her not receiving sympathy or help now.