She subsequently appeared on television as Sarah Walker Laurent on the ABC drama series Brothers & Sisters from 2006 to 2011, for which she was nominated for two additional Primetime Emmy Awards.

In 2016, she appeared in a supporting role in Mel Gibson's biographical war drama Hacksaw Ridge, and in the docudrama miniseries When We Rise, written by Dustin Lance Black.

In addition to acting, she made her directorial debut with the short film Tulip in 1998, and directed several episodes of the Australian television series Nowhere Boys in 2015.

[18] After being rejected from the National Institute of Dramatic Art, Griffiths joined the Woolly Jumpers, a Geelong-based community theatre group.

That same year she starred in My Son the Fanatic, a British film in which she portrayed a tough Yorkshire prostitute who becomes involved with a considerably older Pakistani taxicab driver, played by Om Puri.

[29] While starring on Six Feet Under, Griffiths continued to occasionally appear in the films, playing the supportive housewife of Dennis Quaid in the Walt Disney drama The Rookie (2002), and in the Australian biopic Ned Kelly (2003), opposite Heath Ledger, Geoffrey Rush, and Orlando Bloom.

[30] In the spring of 2002,[31] she appeared in a Melbourne production of Proof by the American playwright David Auburn, for which she earned a Helpmann Award for Best Female Actor in a Play.

In 2006, she became part of the ensemble cast, co-starring alongside Sally Field, Calista Flockhart, Balthazar Getty and Matthew Rhys, of the dramatic series Brothers & Sisters, in which she portrays Sarah Walker, who inherits control of the family business after her father's death.

[34] Griffiths made her Broadway debut in Other Desert Cities,[35] directed by Joe Mantello and co-starring Judith Light, Stockard Channing, and Stacy Keach, which began previews on 10 October 2011, opening on 3 November 2011 in Manhattan.

With discreet adjustments to the text and more penetrating characterizations all around from the sterling cast, the balance between comedy and intense family drama has been fine-tuned in richly satisfying ways".

[43][44] In 2016, Griffiths was cast opposite Guy Pearce and Mary-Louise Parker in the American miniseries When We Rise, a docudrama focusing on LGBT rights, in which she portrays a nurse during the HIV/AIDS epidemic in the United States.

[47] In 2018, she appears in the SBS thriller miniseries Dead Lucky, which was sold for American distribution to the streaming service SundanceNow in April 2018.

[49] In 2024, Griffiths appeared in the final season of ABC political drama Total Control, after appearing in the two previous seasons, she also served as executive producer on the 3 series show..[50] In 2017, Griffiths worked promoting the "No Robe" campaign for the Art Series Hotels, which invited hotel guests to pose for nude portraits in their rooms and have them brought to life by artists.

[52] Griffiths married Australian artist Andrew Taylor on 31 December 2002 in the chapel of her high school, Star of the Sea College, in Melbourne.

Achieving further success overseas, Griffiths was nominated for the Academy Award for Best Supporting Actress in 1999 for her role in the biographical film Hilary and Jackie (1998).