Andrew Luck threw for 227 yards and ran for two touchdowns Thursday as Indianapolis avenged an early season NFL defeat with a 27-10 triumph over division rivals Jacksonville.
The Colts are now 5-1 since head coach Chuck Pagano left the team to undergo treatment for leukemia.
Interim coach Bruce Arians had feared his team might suffer a let-down after an emotional locker-room visit from Pagano after last week's victory over Miami.
Instead, Indianapolis became the latest team to beat up the Jaguars, whose lone victory this season was their 22-17 win over the Colts back in September.
Luck's streak of four straight 300-yard passing games came to an end, but the rookie quarterback delivered on the ground to help the Colts put together their first four-game winning streak since the end of the 2010 season.
Colts defender Darius Butler finished with two interceptions -- returning one for a touchdown -- in the victory.
The week's action continues Sunday, when the Atlanta Falcons, 8-0 for the first time in club history, will launch the second half of their campaign at NFC South division rivals New Orleans.
"We are halfway through the season and I think everybody's focus is just to keep their head down, keep working hard and not worry about anything more than that," quarterback Matt Ryan said after the Falcons beat Dallas on Sunday.
"I think that is one of the reasons we have been successful in the first half of the season. It's going to be important for us to keep doing that to try and be successful in the second half."
The Saints will rely on their own star quarterback, Drew Brees, who is 10-2 against the Falcons since joining the Saints in 2006.
His team breathed new life into their season on Monday when Brees threw for 239 yards and two touchdowns in a 28-13 victory over Philadelphia.
The Eagles and the Cowboys will both be trying to bounce back from last week's defeats when they meet in an NFC East division clash at Philadelphia.
The Eagles, mired in a four-game losing streak, will try to ignite their sputtering offence. They are 29th in scoring with an average of 16.6 points per game, and quarterback Michael Vick was sacked seven times by the Saints last week.
Nor has the Cowboys offense offered much to celebrate. They rank 26th in the league and their loss to Atlanta was their second straight and fourth in five games.
In other games this week, the Super Bowl champion New York Giants, the NFC East leaders, visit Cincinnati, trying to bounce back from a 24-20 home loss to Pittsburgh.
AFC East leaders New England host Buffalo -- who have not won at New England since November of 2000.
Overall, the Bills have lost 11 straight games at New England and have lost 22 of its last 24 games against the Pats.
Denver coach John Fox takes his Broncos to Charlotte -- where he coached the Panthers for nine seasons -- the Broncos attempting to improve on the 5-3 record that has them atop the AFC West.
Other games see Tennessee at Miami, Detroit at Minnesota, San Diego at Tampa Bay, the New York Jets at Seattle, St. Louis at San Francisco, Houston at Chicago and on Monday, Kansas City at Pittsburgh.