It's the third time the Harbaugh brothers have faced off as NFL coaches, but the first since Super Bowl 47 in 2013, when the Ravens beat the San Francisco 49ers 34-31 in New Orleans.
The other regular-season game took place on Thanksgiving night in 2011. The Ravens beat the Niners 16-6 in Baltimore.
Jim Harbaugh left San Francisco after the 2014 season to take over at his alma mater, the University of Michigan. Harbaugh coached at Michigan for nine seasons and won the national title last season before being hired by the Chargers.
He said last week he was thankful for the chance to have another matchup with his brother.
"Walking off the field at that Super Bowl was like, there will be another day. And then there wasn't for many years and it looked like I wouldn't have a chance for another day," he said. "But by the grace of God, I'm back in it and back on a team that has a chance."
The brothers talked for a couple minutes and posed for photos before returning to their teams.
"I love my brother. And I'd lay down my life for my brother. But I would not let him win a football game," Jim Harbaugh told ESPN during a pregame interview. "He wouldn't want it that way. It feels cool and we're ready to have at it."
John Harbaugh said before the game that coaching against his brother is complicated, because sometimes their teams are mirror images of each other.
"It's all the things we love about each other and then its all the things we know about each other that we have to overcome in a game like this," he told ESPN. "He's a great coach. He's a great man. He's a great leader and he's got a great football team, so that makes it complicated.
Their parents, Jack and Jackie Harbaugh, celebrated their 63rd wedding anniversary on Monday. They attended the first two games between the brothers, but are spending Thanksgiving week in Bradenton, Florida, at their daughter Joanie's house.