Portman appeared on Saturday Night Live on March 4, 2006, hosting the show with musical guest Fall Out Boy and special guest star Dennis Haysbert. In a SNL Digital Short, she portrays herself as an angry gangsta rapper (with Andy Samberg as her Flava Flav-esque partner in Viking garb) during a faux-interview with Chris Parnell, saying she cheated at Harvard University while high on pot and cocaine. In another sketch, she portrays a student named Rebecca Hershlag (her actual surname) attending a Bar Mitzvah, and in an installment of the recurring sketch The Needlers (also known as Sally and Dan, The Couple That Should Be Divorced), plays a fertility specialist (her father's profession). V for Vendetta opened in early 2006. Portman portrayed Evey Hammond, a young woman who is saved from the secret police by the main character, V. Portman worked with a voice coach for the role, learning to speak with an English accent, and had her head shaved. Maxim magazine named Portman #33 on its annual Hot 100 list, citing her V for Vendetta hairstyle as a huge accomplishment proving "you don't need hair to be hot."

Portman has commented on V for Vendetta's political relevance, and mentioned that her character, who joins an underground anti-government group, is "often bad and does things that you don't like" and that "Being from Israel was a reason I wanted to do this because terrorism and violence are such a daily part of my conversations since I was little." She said the film "doesn't make clear good or bad statements. It respects the audience enough to take away their own opinion". Both Goya's Ghosts and Free Zone received limited releases in 2006. Portman starred in the children's film Mr. Magorium's Wonder Emporium, which began filming in April 2006 and was released in November 2007; she has said that she was "excited to do a kids' movie." In late 2006, Portman filmed The Other Boleyn Girl, a historical drama in which she plays Anne Boleyn; Eric Bana and Scarlett Johansson co-starred in the film. She was also named one of the hottest women of film and TV by Blender Magazine.

In 2006, she filmed Wong Kar-wai's road movie My Blueberry Nights. She won acclaim for her role as gambler Leslie, because "for once she's not playing a waif or a child princess but a mature, full-bodied woman,...but she's not coasting on her looks;...She uses her appeal to simultaneously flirt with and taunt the gambler across the table". Portman had a small role in the 18th season of The Simpsons as the voice of Bart Simpson's first girlfriend, Darcy. She also appears in Paul McCartney's music video "Dance Tonight" from his 2007 album Memory Almost Full, directed by Michel Gondry. Portman co-starred in the Wes Anderson short film Hotel Chevalier, opposite Jason Schwartzman, in which she performed her first nude scene. She is scheduled to star opposite Tobey Maguire and Jake Gyllenhaal in the drama film Brothers, a remake of the 2004 Danish film of the same name. In May 2008 Portman served as the youngest member of the 61st Annual Cannes Film Festival jury.

• 17 Photos of Isabel (2009) (filming) .... Emilia Greenleaf
• Brothers (2009/II) (post-production) .... Grace Cahill
• New York, I Love You (2008) .... Rifka
  ... aka New York, je t'aime (France: literal title)
• The Other Boleyn Girl (2008) .... Anne Boleyn
• Mr. Magorium's Wonder Emporium (2007) .... Molly Mahoney, the Composer
• The Darjeeling Limited (2007) .... Jack's Ex-Girlfriend
• Hotel Chevalier (2007) .... Jack's Girlfriend
  ... aka Part 1 of 'The Darjeeling Limited' (USA: subtitle)
• My Blueberry Nights (2007) .... Leslie
• "The Simpsons" .... Darcy (1 episode, 2007)
       - Little Big Girl (2007) TV episode (voice) .... Darcy
• Goya's Ghosts (2006) .... Inés/Alicia
  ... aka Fantasmas de Goya, Los (Spain: dubbed version)
• Paris, je t'aime (2006) .... Francine (segment 'Faubourg Saint-Denis')
  ... aka Paris, I Love You (Hong Kong: English title)
• V for Vendetta (2005) .... Evey
  ... aka V for Vendetta: At the IMAX (UK: IMAX version)
  ... aka V for Vendetta: The IMAX Experience (USA: IMAX version)
  ... aka V wie Vendetta (Germany)
• Free Zone (2005) .... Rebecca
  ... aka Free Zone (France)