The Fast And The Furious actress will play Chuck Bartowski's college girlfriend Jill, who slept with his best mate and is credited with sending his life into a downward spiral.
Executive producer Josh Schwartz said Brewster would appear in at least three episodes. "[Chuck] always has imagined seeing her again, and being able to impress her with all he's accomplished," he added.
"Unfortunately, when he does meet her, he's doing a computer install and she's a brilliant, successful, beautiful doctor working to create antibodies to horrible diseases.
"The part is funny, romantic, there's action and cool twists and emotional drama. It's the juiciest arc we've done yet and one that ties very deeply into the mythology of the show and the character of Chuck."
The second season of Chuck will begin on NBC in September. The first has aired in the UK on Virgin 1.