The actor, who bowed out of sitcom That '70s Show earlier this week, will play an as-yet unknown role in the third film of the franchise, which is due for release in 2007.
"I couldn't be more excited about the direction we are taking the continuing adventures of Peter Parker," said director Sam Raimi. "Topher Grace is an extraordinarily talented actor and will be perfect for the complexities of the role we are developing."
Thomas Haden Church, last seen in the acclaimed movie Sideways, is another new addition to the cast.
Meanwhile, Marvel chairman Avi Arad has dismissed reports that the next two sequels will be filmed back-to-back, Matrix-style, to save on overall production costs.
"Not true," said Arad. "No, it doesn't make sense ... I don't believe it. I don't believe you really save money. What you do, in essence, is you ensure that you book your stars for long enough."
He added: "Spider-Man 3 has to be bigger than 1 and 2. So storywise it's already bigger, the characters in it are already bigger ... it will already be a handful to [complete it by] May 2007."