Manning completed a club-record 39 passes on 59 attempts, finishing with 397 yards as AFC West-leading Denver (11-2) officially entered the post-season with the conference's best record.
Matt Prater went 3-of-3 on field goal tries, including an NFL-record 64-yard boot in the first half that came during a run of 24 unanswered Broncos points.
Eric Decker hauled down eight passes for 117 yards with a score.
Wes Welker made five grabs for 61 yards and a touchdown before exiting at halftime with a concussion.
The Titans (5-8) saw their post-season hopes dim with a fourth loss in five games as Ryan Fitzpatrick was limited to 172 yards on 13-of-24 passing with a touchdown and an interception.