Also in 1996, Mortimer appeared in her first feature film opposite Val Kilmer in The Ghost and the Darkness, and in the coming-of-age story, The Last of the High Kings.

In 1998 she appeared as Kat Ashley in Elizabeth, and played Miss Flynn in the television mini series Cider with Rosie, which was adapted for television by her father. In 1999, she played three roles: she was the “Perfect Girl” dropped by Hugh Grant in Notting Hill; Esther in the television mini series Noah’s Ark; and Angelina, the star of the film within a film in Scream 3.

In 2000, Mortimer was cast as Katherine in Kenneth Branagh’s musical adaptation of Love’s Labour’s Lost, where she met actor and future husband Alessandro Nivola. She took on her biggest role in an American film to date, playing opposite Bruce Willis in Disney’s The Kid. In 2002, she had a major role in The 51st State (also known as Formula 51), starring opposite Samuel L. Jackson and Robert Carlyle.

In 2000, Mortimer met American actor Alessandro Nivola while both were starring in Love’s Labour’s Lost. The couple married in the village of Turville in the Chilterns, Buckinghamshire, on 3 January 2003. Mortimer gave birth to their first child on 26 September 2003 and their second child in 2010. They live with their two children in Boerum Hill, Brooklyn. Mortimer became an American citizen, for tax reasons, circa 2010.

In 2003, Mortimer appeared in Stephen Fry’s film Bright Young Things. In 2004, Mortimer played the female lead in the film Dear Frankie. In 2005, she played a major role as the oblivious spouse of Jonathan Rhys Meyers’s adulterer in Woody Allen’s Match Point, as well as voiced young Sophie in the English-dubbed version of Howl’s Moving Castle. In 2007 she played a supporting role in Lars and the Real Girl as the supportive sister-in-law of Ryan Gosling’s title character. She appeared in The Pink Panther in 2006 and in its 2009 sequel. In the last three episodes of the first season of 30 Rock, she played Phoebe, the mysterious love interest of Alec Baldwin’s character, Jack Donaghy.

Mortimer played an aspiring actress opposite Andy García in City Island (2009) and as Rachel Solando in Martin Scorsese’s 2010 film Shutter Island. She played Leonie Gilmour in Leonie, released in the autumn of 2010. In 2011, she had a role in Our Idiot Brother as Liz, the sister of Paul Rudd’s titular character. Also in 2011, she started work with the acclaimed screenwriter and producer Aaron Sorkin as Mackenzie McHale in HBO’s The Newsroom. In January 2013 it was announced that Mortimer would be co-creating and starring in the comedy series Doll & Em for Sky Living, along with her longtime friend, actress and comedian Dolly Wells.