De Rossi's first significant role was as a young and impressionable model in the Australian 1994 film Sirens. That same year, she portrayed an Australian reporter who inspires a protest against Frank Sinatra during a concert tour in The Night We Called It a Day.
Soon afterward, she moved to Los Angeles and won guest roles on several TV shows and a permanent role in Nick Freno: Licensed Teacher, before landing a part in the film Scream 2. From 2003–06, de Rossi starred as Lindsay Bluth Fünke on Fox Television's Arrested Development. Kennedy, Jr.'s wife, Carolyn Bessette-Kennedy, in the made-for-TV movie America's Prince: The John F. In 2005 de Rossi portrayed Zela, a fortune-teller, in the Wes Craven thriller Cursed.
Shonda, Betsy and the cast have been incredibly supportive of my decision. De Rossi was married to documentary film-maker Mel Metcalfe, from 1996 to 1999, initially part of a plan to get a green card, though she did not go through with the plan.
She said about the marriage that "it just obviously wasn't right for me." From 2001 to 2004, de Rossi dated director Francesca Gregorini, the daughter of Barbara Bach and the stepdaughter of Ringo Starr.
De Rossi and Gregorini broke up in late 2004 because de Rossi began dating De Generes, whom she met backstage at an awards show.
In 2005, she opened up publicly about her sexual orientation in interviews with Details and The Advocate.
De Rossi herself made the decision to depart the Scandal series, saying, "I am incredibly grateful for my time here at Scandal.
I will miss playing Elizabeth North but I've made the decision to focus on a business opportunity. " Creator Shonda Rhimes added, "I have been a fan of Portia's for years and it was an honor to have her join our Scandal family." In May 2018, de Rossi announced on The Ellen De Generes Show that she would be retiring from acting, though she later elaborated that she would make an exception for future seasons of Arrested Development.
She declined to publicly discuss the relationship or her sexual orientation at the time.
In February 2012, it was announced that ABC had ordered a pilot for a new drama series The Smart One, one of whose executive producers was listed as Ellen De Generes, and which featured de Rossi in a leading role.
The actress was to star as a "brilliant and successful woman who begrudgingly goes to work for her less-brainy but more popular sister – a former beauty queen, weather girl and now big-city Mayor." Six years after the series was canceled by Fox, filming for a revived fourth season of Arrested Development began on 7 August 2012, and de Rossi reprised her role as Lindsay Bluth Fünke.
She was talking about her former girlfriend’s death.
She recalled: Ellen was working as a waitress in New Orleans at that time.