Jackson completed 20 of his 25 passes and added a team-best 45 rushing yards to spoil the debut of Browns head coach Kevin Stefanski. Cleveland hasn't won a season opener since 2004.
"The guy was incredible last year," said Ravens tight end Mark Andrews, who had two receiving touchdowns Sunday. "To me, he's obviously the best player in the world, and his arm reflects that."
"Lamar Jackson just played a phenomenal game in every single way," Ravens head coach John Harbaugh said. "He was probably the biggest difference in the game."
Browns quarterback Baker Mayfield completed 21 of 39 passes for 189 yards and was sacked twice. He threw an interception on the Browns' opening possession -- the first of three Browns turnovers in the game.
Those turnovers -- along with two missed kicks by Austin Seibert and a failed fake punt call by Stefanski -- also contributed to the rout.
"Very disappointed, obviously," Stefanski said. "But credit to the Baltimore Ravens. They deserved to win. They outcoached us, they outplayed us. We did a lot of things losing teams do."
Mark Ingram II led the Ravens backfield with 10 carries for 29 yards. Rookie tailback J.K. Dobbins was right behind him with seven rushes for 22 yards and two scores.
Ravens wideout Marquise Brown had five catches for a team-high 101 yards. Willie Snead IV had four grabs for 64 yards and one receiving touchdown.
Browns receiver Jarvis Landry led the team with five receptions for 61 yards. Superstar wideout Odell Beckham Jr. was targeted 10 times but tallied just three catches for 22 yards.
Cleveland tight end David Njoku notched three receptions for 50 yards and the team's lone touchdown -- a 1-yard pass from Mayfield late in the first quarter.