He is known for his roles as Eric Forman in the teen sitcom That '70s Show (1998–2005) and Eddie Brock / Venom in Sam Raimi's superhero film Spider-Man 3 (2007).

Grace won the National Board of Review's 2004 award for Breakthrough Performance Actor for his work in In Good Company and P.S.

"[15] In 2010, Grace appeared in the ensemble comedy Valentine's Day and played the character of Edwin in Predators.

[18] 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.

[19] In 2014, Grace starred in the indie thriller The Calling, alongside Susan Sarandon,[20] and appeared in Christopher Nolan's sci-fi adventure Interstellar, in a supporting role.

[22][23] Grace co-starred in the comedy film American Ultra (2015), alongside Jesse Eisenberg and Kristen Stewart, playing a CIA agent.

[24] That same year, he co-starred in Truth, with Robert Redford and Cate Blanchett, 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.

[25] 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.

[29] Grace has long held an interest in making fan edits of popular films, particularly those involving Star Wars.

The edit utilized original footage, music from the Clone Wars series, and a portion from Anthony Daniels' audiobook recordings.

[citation needed] In 2014, he created a cut of Boogie Nights that served as a reconstruction of the character Brock Landers' fake movie Angels Live in My Town.

"[33] He specifically edited this as a way to relax while portraying David Duke in Spike Lee's BlacKkKlansman.

[citation needed] In 2019, Grace and editor Jeff Yorkes started a Twitter account for "Lou's Cafe", the pseudonym by which the two credit their work.