Newton continued his trend of turning the ball over, throwing three interceptions and looking uncomfortable throughout the game. The Patriots replaced him with Jarrett Stidham with 13:20 left in the final quarter.
Newton completed 9 of 15 pass attempts for 98 yards before being pulled. The 33-6 defeat marked the worst home loss in Bill Belichick's 21-year tenure as head coach of the Patriots.
Despite Newton's turnover issues, Belichick said that Newton "absolutely" remains the team's starter moving forward. The longtime Patriots coach said he decided to put Stidham in the game to get him more experience.
Entering Sunday's game against the 49ers, the Patriots had lost by 20 or more points at home only three times under Belichick -- with two of those defeats coming in 2008. Former Patriots quarterback Tom Brady was out for the season because of a torn ACL that year.
"I've just been pressing. The energy has definitely been off for me, and at times it's not rewarding when you're just going out there with this aura about yourself that's not you," Newton said. "I love playing this game, I have fun playing this game, but the performances here haven't been delightful for me.
"... A lot of things start and stop at that position, and I have put this team in a rut with the performances here."
In the team's 2-4 start, the Patriots have thrown only three touchdown passes -- the fewest in the NFL -- and 11 interceptions, the most in the league.
49ers quarterback Jimmy Garoppolo completed 20 of his 25 pass attempts for 277 yards and two interceptions. He connected with rookie Brandon Aiyuk six times for 115 yards.
Jeff Wilson Jr. had 112 rushing yards and three touchdowns on 17 carries for the Niners. George Kittle, who received praise from Belichick earlier in the week, notched five receptions for 55 yards.
In place of Newton, Stidham was 6 of 10 passing for 64 yards and one pick. Damien Harris led the team with 58 rushing yards on 10 carries.