Keddie had guest roles early in her career in various television dramas, including her first roles in Five Mile Creek (1985), Fortress (1986) and Janus (1994). She played the role of Marriane Sheridan in Blue Heelers (season 3, episode 21) airing on 18 June 1996 and Good Guys, Bad Guys (1997). From 1997 to 1998, she came to the attention of senior network television producers, appearing in State Coroner. Following this, she had a recurring role in Stingers from 2000 to 2004.
Making her theatre debut for the Melbourne Theatre Company in 1998 in Patrick Marber's Closer, Keddie went on to appear in Cyrano de Bergarac, Les Liaisons dangereuses, Birthrights, Great Expectations, The Seagull and Hannie Rayson's Life After George. Her performances in the 2005 Melbourne Theatre Company production of Les Liaisons dangereuses, and the Playbox's The Ishmael Club, both earned her Green Room Award nominations.
Keddie's big break came in 2004, where she had a leading role in Love My Way, a drama series airing on Foxtel. The series ended in late 2007. This role led to Keddie being nominated for various awards for playing the part of Julia Jackson, a woman who struggles to cope with her own identity in the midst of family tragedy. Keddie's award win came at the end of Love My Way's third series in 2006.
In 2007 Keddie starred alongside Jay Bowen in the Melbourne Theatre Company's play The Glass Soldier written by Hannie Rayson.
In 2009, Keddie appeared in three different roles. She portrayed police officer Liz Cruickshank in the television drama Underbelly: A Tale of Two Cities and Journalist Jacinta Burns, in the TV series Rush, as well as Dr Carol Frost in X-Men Origins: Wolverine.
In 2010, Keddie depicted author Blanche d'Alpuget in Hawke, a telemovie about the premiership of Bob Hawke (the Prime Minister of Australia, 1983–91). She also became the star of the drama series Offspring, which began airing in August 2010. In April 2011, she had the leading role of Ita Buttrose in ABC1's telemovie Paper Giants: The Birth of Cleo, the story of Buttrose's rise to success as the Editor of Cleo magazine.
She married actor and musician Jay Bowen in January 2007. The pair separated in December 2011. In April 2014, she married Artist Vincent Fantauzzo. On 19 November 2014 she announced at the GQ Men's Award that she was pregnant. On 1 March 2015, the couple welcomed their first child, a boy named Valentino Fantauzzo.
As of 2015, she has taken out the 'Silver Logie Award for Most Popular Actress' five times in a row. Keddie won the 2013 Gold Logie award for Most Popular Personality on Australian Television, for her role as Dr Nina Proudman in the Network Ten drama Offspring. She was considered "third time lucky" after previously being nominated twice for the Gold Logie. Keddie has a total of 7 Logie Awards as of May 2015.
