The Steelers, who held together during Roethlisberger's four-game suspension with solid defensive play, host a struggling Cleveland Browns team that is expected to give rookie quarterback Colt McCoy his first league start.
Roethlisberger, who was suspended following accusations of sexual assault, rejoined the Steelers on Oct. 4 ahead of their bye week and has reportedly been sharp in team practice.
Pittsburgh won their first three games of the season before suffering their only loss, a 17-14 defeat by the Baltimore Ravens after a last-minute touchdown.
Before the season began, the Dallas Cowboys and Minnesota Vikings were both considered among the favorites to represent the NFC in the Super Bowl.
But whichever team comes up short in Sunday's match up will slip to 1-4 and need a string of victories thereafter to get their season back on track.
The Vikings have listed starting quarterback Brett Favre as questionable for the game, jeopardizing his NFL record of 289 consecutive regular-season starts.
Dallas, bidding to become the first team to play in their home stadium in the Super Bowl, are coming off a 34-27 loss to the Tennessee Titans while the Vikings fell 29-20 to the New York Jets on Monday.
New York will put their much vaunted defense and rushing attack to the test when they bid to win a third successive game on the road against Kyle Orton and the Denver Broncos on Sunday.
The AFC East-leading Jets have not started a season 3-0 on the road since 2001 and they face a tough task in the rarefied heights of Denver against the NFL's top-ranked passing attack.
A further question mark for New York hangs over the fitness of their All-Pro cornerback Darrelle Revis who was listed as questionable for Sunday with a lingering hamstring strain.
"He's either healthy enough to play or he's not," Jets head coach Rex Ryan said on Friday.
"We'll have a light practice and then we'll go from there. I've been impressed with the way he's looked the past couple days. We'll see what happens when we get out there." Revis strained his right hamstring on Sept. 19 and missed the next two games before returning for Monday's victory over Minnesota.
He has since described his leg as "very sore" and was only able to practice on a limited basis this week.
However, Revis was the only fitness concern for a 4-1 Jets who, with running backs LaDainian Tomlinson and Shonn Greene setting the tone, lead the league in rushing yards per game.
"We're built to run the football," Ryan said. "We don't care if you know it's coming or not. That's part of our philosophy and our mentality, that you can put (defenders) down there if you want, but we're still going to run it, and we're going to be successful at running it. That's what we do."
The Super Bowl champion New Orleans Saints, who lie third in the NFC South after a shaky 3-2 start, face a daunting challenge when they visit the Tampa Bay Buccaneers on Sunday.
While the struggling Saints were beaten 30-20 by the Arizona Cardinals last week, the upbeat Buccaneers came from behind to stun the Cincinnati Bengals 24-21 for their third win in four games.
Among the other games on Sunday are the Baltimore Ravens (4-1), who visit the New England Patriots (3-1) and the Philadelphia Eagles (3-2), who host the Atlanta Falcons (4-1).
The Kansas City Chiefs (3-1), who surrendered the NFL's last unbeaten record with their 19-9 loss to the Indianapolis Colts on Sunday, visit the Houston Texans (3-2).
