If McCown is to come anywhere close to replicating one of the best efforts in Cleveland Browns history, he'll have to do it against a Denver defense that has helped mask Manning's issues during the Broncos' 5-0 start.
Denver's NFL-best pass rush might not be as dominant, though, as all signs point to DeMarcus Ware having to sit out Sunday's meeting in Cleveland.
McCown threw for a Browns regular season-record 457 yards and two touchdowns while running for another score in last week's 33-30 overtime win over Baltimore, completing 36 of his career-high 51 attempts.
The 36-year-old has completed 68.1 percent of his passes for 1,154 yards, six touchdowns and one interception over his last three after missing a week with a concussion. His latest effort helped Cleveland (2-3) bounce back from a pair of defeats that came by a combined 10 points.
McCown practiced this week despite a left ankle injury suffered in overtime, which could affect his mobility against a Broncos team that leads the NFL with 22 sacks.
Denver is also allowing the fewest yards per game at 278.0 and has forced a league-high 14 turnovers. Chris Harris Jr. ran an interception back 74 yards for a touchdown in the fourth quarter of last week's 16-10 victory over Oakland.
Ware was carted off the field in the second quarter with back spasms and Kubiak said he's day to day. Linebacker Von Miller doesn't see it that way, saying publicly that he expects Ware to miss "a couple weeks," and other teammates have expressed they're preparing to play without him.
If Ware does sit out, he'll have extended time to recover with Denver heading into its bye.
"Anytime you can rush the passer the way they do, you have to be able to establish some type of run. So that will be important to us," Browns coach Mike Pettine said. "Part of it, too, is to get ahead of the sticks, to not be in those situations."
Denver didn't score an offensive touchdown last week as Manning finished with 266 yards and two interceptions. He's thrown six TDs and seven picks - tied for second-most in the league - and his completion percentage of 63.5 ranks 20th.
The Broncos don't seems worried.
''I think in coaching you're always searching for perfection and obviously we're far from it,'' Kubiak said. ''We've got some tremendous things going on defensively and we're battling offensively right now. But it's hard to win in this league, and I've been doing it long enough to know you'd better appreciate it.''
Manning has thrown at least one interception in each of the first five games for the first time since 1999, when he did so in six straight to open the year, his second in the league. He's also facing the challenge of having to overcome a struggling running game that ranks 31st in yards per attempt at 3.31.
''(The offense is) going to pick it up," Harris said. "We have faith in Peyton. We all have faith in him. We know it's not just him. We know we need to get the run game going, get everybody going.
''We know that once they start clicking, it's going to be over.''
This appears to be a prime week for the running game to bust out. The Browns are tied for last in the league in opponents' average yards per carry at 5.05 and surrendered a season-worst 181 to the Ravens.
Cleveland's opponents have scored six rushing touchdowns. One of Denver's two scores on the ground came on Ronnie Hillman's 72-yard run against Minnesota on Oct. 4, with that play accounting for more rushing yards than the Broncos have had in each of their other four games.
These teams haven't met since Manning threw for 339 yards and three touchdowns in Denver's 34-12 victory in 2012, and Pettine isn't putting it past the veteran quarterback to have another performance like that despite his early struggles.
"Anytime you install a new offense, right in the beginning, there are going to be some hiccups, even with someone of his caliber," Pettine said. "When I see him, especially the third-down stuff, the two-minute when they have gone no-huddle, is when you see the vintage Peyton."