"He at least has an ACL and probably more," Harbaugh said. "We said a prayer over him, and he'll find a way to come back stronger than before."
Jefferson injured his left knee with 9 minutes, 23 seconds left in the fourth quarter and was carted off to the locker room. One of the leaders on defense, Jefferson was in charge of relaying the defensive calls to teammates.
This has been a challenging year for Jefferson, who was rated as the sixth-worst safety in the NFL entering Week 5, according to Pro Football Focus. He entered Sunday's game as the second-leading tackler for Baltimore.
"To see him go down like that, it's definitely a blow to the team," safety Earl Thomas II said. "It definitely hurts the team."
Chuck Clark, who has two starts in three seasons, is expected to replace Jefferson.
This is just the latest injury to the Ravens' secondary, which lost nickelback Tavon Young (neck) for the season and has been without cornerback Jimmy Smith (knee) for four straight games.
Linebacker Matthew Judon said of Jefferson, "I love that guy and he loves football. It just really sucks. It really does."