Coach Jon Gruden told reporters Wednesday Griese's knee will require season-ending surgery.
Third-year pro Chris Simms will take over as the Buccaneers' starting signal-caller.
"We did everything we could, and Brian wanted to do everything also, to get as much information as we could," Gruden said. "Today's really a sad day in a lot of ways because we do have closure on Griese's situation, but we're very excited for Chris Simms. He had a good workout (Wednesday) and we're going to rally around him the best we can."
For the season, Griese -- who sought other medical opinions before deciding on surgery -- passed for 1,136 yards, seven touchdowns and seven interceptions in six games. The Buccaneers acquired veteran Tim Rattay from San Francisco before the league's trading deadline on Tuesday.