Backup signal-caller Jameis Winston replaced Brees to start the second half after the injury. Brees remained suited up on the Saints' sideline while Winston was in the game, but he never returned.
Brees had been limited during practice over the last two weeks because of a right shoulder injury. The team initially said he was questionable to return.
The 41-year-old Brees remained in the game after taking a huge hit that led to a personal foul penalty on 49ers defensive lineman Kentavius Street with under nine minutes left in the first half. Taysom Hill, however, took the Saints' next two snaps at quarterback after that play.
Brees reentered the game to pitch the ball to running back Alvin Kamara for a two-yard score. He played the next series, then took a knee to send the contest into halftime before watching from the sideline for the remainder of the game.
The 13-time Pro Bowl selection has missed only six games due to injuries in his 20-year NFL career. He sat out five games in 2019 because of a torn ligament in the thumb on his throwing hand.
Despite missing Brees, the Saints earned a 27-13 win over the 49ers to move to 7-2 this season.