Grace was cast as Eric Forman on Fox's That '70s Show, which debuted in 1998. He played the role regularly until the show's 7th season, when his character was written out and replaced with a new character named Randy Pearson (Josh Meyers). Grace made a brief guest appearance in the final episode.
Grace played a prep school student who introduces his girlfriend to freebasing in director Steven Soderbergh's 2000 film Traffic, as well as having uncredited cameos as himself in Soderbergh's Ocean's Eleven and its 2004 sequel, Ocean's Twelve. "The joke is that you're supposed to play the worst version of yourself and I don't think too many people are comfortable with that. I never thought for a second that people were really going to think that's what I was like. I think that people will know that I was faking it in those movies", he told Flaunt magazine in 2007.
He planned to cameo in Ocean's Thirteen. However, due to his role in Spider-Man 3, he had to abandon these plans. As Grace said, "I was doing reshoots on Spider-Man 3. I was bummed. I actually talked to Steven Soderbergh about that and we had a thing and then I couldn't do it." He appeared in director Mike Newell's 2003 film Mona Lisa Smile.
In 2004, Grace played the leading roles in Win a Date with Tad Hamilton! and In Good Company. That same year, he starred in P.S., which received only a limited theatrical release. Grace won the National Board of Review's 2004 award for Breakthrough Performance Actor for his work in In Good Company and P.S.
On January 15, 2005, Grace hosted Saturday Night Live.
In 2007, Grace portrayed Eddie Brock/Venom in Spider-Man 3, directed by Sam Raimi. Grace himself was a fan of the comics and read the Venom stories as a child. In 2009, Grace became the subject of a recurring column on the entertainment/pop culture site Videogum, entitled "What's Up With Topher Grace?"
In 2010, Grace appeared in the ensemble comedy Valentine's Day and played the character of Edwin in Predators.
In 2011, Grace appeared in the 1980s retro comedy Take Me Home Tonight. He co-wrote the script and co-produced the film. Grace also starred opposite Richard Gere in the spy thriller The Double.
In 2012, Grace starred alongside Mary Elizabeth Winstead and Matthew Gray Gubler in the social film The Beauty Inside, which won a Daytime Emmy Award for Outstanding New Approach to an Original Daytime Program or Series in 2013. The film was directed by Drake Doremus and written by Richard Greenberg.
In 2014, Grace starred in the indie thriller The Calling, alongside Susan Saran and appeared in Christopher Nolan's sci-fi adventure Interstellar, in a supporting role.
In October 2013, Grace joined HBO comedy pilot People in New Jersey with Sarah Silverman, but in January 2014, the pilot was passed on.
Grace co-starred in the comedy film American Ultra (2015), alongside Jesse Eisenberg and Kristen Stewart, playing a CIA agent. That same year, he co-starred in Truth, with Robert Redford and Cate Blanchett, and based on the story of CBS's 60 Minutes report that George W. Bush had received preferential treatment to keep him out of the Vietnam War. Grace played Mike Smith, a researcher on the story.
In January 2018, Grace joined the supernatural-thriller Delirium, which centers on a man recently released from a mental institute who inherits a mansion after his parents die. After a series of disturbing events, he comes to believe it is haunted. In August 2018, Grace portrayed David Duke in the biographical crime film BlacKkKlansman, directed by Spike Lee, alongside John David Washington and Adam Driver. In 2019, he played Billy Bauer in the 2nd episode of Black Mirror’s 5th season, titled "Smithereens". In 2020, Grace was cast in ABC's Home Economics pilot. On April 30, 2022, it was announced that Grace would have a guest appearance in the follow-up sitcom, That '90s Show.
