Brewster grew up in Massachusetts and moved to New York City to attend Parsons School of Design. During her first year, she made her acting debut and eventually dropped out of design school to pursue her acting career. In the mid-1990s, Brewster moved to San Francisco and enrolled in acting classes.
Brewster hosted a late-night talk show in the San Francisco Bay Area in the mid-1990s called The Paget Show for 65 episodes. She first came to prominent attention in her recurring role as "Kathy" in the fourth season of NBC's Friends.
Brewster had a long run with the show Criminal Minds, playing multilingual Supervisory Special Agent Emily Prentiss until the show's sixth season when she and A. J. Cook were released from their contracts by CBS in a cost-cutting move. Owing to complaints from fans, both she and Cook were rehired and kept for the following season. In February 2012, Brewster announced via Deadline that she was leaving Criminal Minds at the end of the season to pursue a possible career in comedy television.