Browns quarterback Baker Mayfield completed just 8 of 22 passes for 100 yards and threw two interceptions in the setback at Levi's Stadium in Santa Clara, Calif. The 49ers out-gained the Browns 446 yards to 180 yards.
"You're not doing your job anytime you stop yourself which seems to be our biggest problem right now obviously," Mayfield told reporters. "When you do that against a team of that caliber, you're not going to have a lot of success."
Rookie defensive end Nick Bosa had two of the 49ers' four sacks on Mayfield in the lopsided victory.
"[Mayfield] was panicking, double clutching, rolling back and forth, we had him rattled all game," Bosa said.
Running back Matt Breida put San Francisco (4-0) on the board with an 83-yard touchdown run on the 49ers' first offensive play. Quarterback Jimmy Garoppolo connected with Matt Breida on a 5-yard touchdown pass for a 14-0 first quarter lead. Cleveland (2-3) answered with a 30-yard field goal from Austin Seibert at the start of the second quarter.
Tevin Coleman pushed the lead to 21-3 with a 19-yard rushing touchdown for the final points of the first half, and Garoppolo hit tight end George Kittle for a 22-yard touchdown on the first drive of the second half.
Niners kicker Robbie Gould hit a 44-yard field goal with 5:13 remaining to give San Francisco their final advantage.
Garoppolo completed 20 of 29 passes for 181 yards and threw two scores in the win. Breida ran for 114 yards and scored twice for San Francisco. Coleman had 97 yards and a score on 16 carries.
"I think we've got the right guys," 49ers coach Kyle Shanahan said. "I think [Monday] was a little lopsided game, but the league is too hard to be overconfident. Every week is a tough week and we've got a lot of work to do."