Betts, the reigning AL MVP, hit leadoff in all 131 games he started this past season. He has made 32 career starts batting second, most recently in September 2017.
"I think we're going to maximize Mookie in a different spot. Flip-flop them, Beni leading off and Mookie hitting second. Talked to him, it makes sense," manager Alex Cora said.
"And I know Beni's OK with it. But if you play 162 games, you're going to come up 162 at-bats with nobody on," said. "And last year, what I wanted from him in the leadoff spot, we accomplished. It's a different season and we have to make adjustments, and that's where we're going to go."
Benintendi hit leadoff 21 times in 2018, most of which came while Betts was on the disabled list with a left abdominal strain. The Red Sox left fielder hit .322 with five HRs and 15 RBIs in those games, with a .979 OPS.
The Associated Press contributed to this report.