As a supporting actress, Graham was cast in a number of parts that brought her attention, including Nadine in the 1989 film Drugstore Cowboy. In 1991, she appeared in the TV series Twin Peaks as Annie Blackburn, Dale Cooper's second-season love interest. However, her breakthrough role was that of 1970s porn starlet Roller Girl in 1997's Boogie Nights, in which she appeared in scenes with frontal nudity and received several award nominations. Her first starring role was in 1999 as Felicity Shagwell in Austin Powers: The Spy Who Shagged Me. She also appeared in the music video for Lenny Kravitz's cover of "American Woman" by The Guess Who. More recently, she starred as Mary Kelly in the 2001 film From Hell, based on the story of Jack the Ripper.

Although Graham has been featured in mainstream films, she has also been cast in a number of independent films. Some of those films, like 2002's The Guru, have brought her critical praise. She also starred opposite Joseph Fiennes in the less successful Killing Me Softly. In 2001, Graham was named by People as one of the "50 Most Beautiful People in the World".

Graham also played herself on one episode of the TV series Sex and the City. She was given special guest-star status on several episodes of NBC-TV's Scrubs during its fourth season (2004–2005), and also appeared in a small role as a teacher in an episode of Fox's Arrested Development. In 2005, Graham became the spokeswoman and TV model for the Garnier brand of hair care products. Graham's print ad for Skyy vodka, which was photographed in 2003 (titled "#3, Entourage") is still appearing in national magazines today as well. Graham also appeared in Anger Management (2003) as Kendra, the girl in a Boston bar.

Graham starred in the ABC-TV comedy series Emily's Reasons Why Not, in 2006. However, ABC-TV announced that the show was canceled after its first airing on January 9, 2006. Because they print their covers weeks in advance, and they did not expect the quick cancellation, Life did a cover story on Graham two weeks later in their January 27, 2006 issue, and they referred to her as "TV's sexiest star". Billboard ads also remained in place promoting the show weeks after the cancellation. Graham voiced the character of Antonia Bayle in the online role playing game EverQuest 2.

• The Hangover (2009) (filming)
• Boogie Woogie (2009) (post-production) .... Beth Freemantle
• Ex-Terminators (2009) (post-production) .... Alex
• Son of Mourning (2008) (post-production)
  
• "Emily's Reasons Why Not" .... Emily Sanders (6 episodes, 2006-2008)
       - Why Not to Hire a Cute Male Assistant (2008) TV episode .... Emily Sanders
       - Why Not to Cheat on Your Best Friend (2008) TV episode .... Emily Sanders
       - Why Not to Date Your Gynocologist (2008) TV episode .... Emily Sanders
       - Why Not to Date a Twin (2008) TV episode .... Emily Sanders
       - Pilot (2006) TV episode .... Emily Sanders
        (1 more)
• Baby on Board (2008)
• Miss Conception (2008) .... Georgina Salt
  ... aka Last Minute Baby (Germany: TV title)
  ... aka Miss Conception (USA: new title)
• Have Dreams, Will Travel (2007) .... Aunt
• Adrift in Manhattan (2007) .... Rose Phipps
• Broken (2006/I) .... Hope
• Gray Matters (2006/I) .... Gray Baldwin
• Bobby (2006) .... Angela
• The Oh in Ohio (2006) (uncredited) .... Justine, Sex Shop Clerk
• Mary (2005/I) .... Elizabeth Younger
  ... aka Mary (France)
• Cake (2005/I) .... Pippa McGee
• "[scrubs]" .... Dr. Molly Clock (9 episodes, 2004-2005)
       - My Best Laid Plans (2005) TV episode .... Dr. Molly Clock
       - My Last Chance (2004) TV episode .... Dr. Molly Clock
       - My Common Enemy (2004) TV episode .... Dr. Molly Clock
       - My Cake (2004) TV episode .... Dr. Molly Clock
       - Her Story (2004) TV episode .... Dr. Molly Clock
        (4 more)
• EverQuest II (2004) (VG) (voice) .... Antonia Bayle - Queen of Qeynos
• Blessed (2004) .... Samantha Howard
• "Arrested Development" .... Beth Baerly (1 episode, 2004)
       - Shock and Aww (2004) TV episode .... Beth Baerly
• Hope Springs (2003) .... Mandy
• Anger Management (2003) (uncredited) .... Kendra
• The Guru (2002) .... Sharonna
  ... aka Gourou et les femmes, Le (France)
• Killing Me Softly (2002) .... Alice
• Alien Love Triangle (2002) .... Elizabeth
• From Hell (2001) .... Mary Kelly
• Sidewalks of New York (2001) .... Annie
• Say It Isn't So (2001) .... Josephine Wingfield
• Committed (2000) .... Joline
  ... aka Non Stop Girl