"It is one heck of a blow," Pagano said. "You don't want to lose anybody, especially your starting quarterback. Our guys will respond like they always do. We've been through a ton already this season and in the past, and we'll get through it. We'll get through it."
Pagano said the injuries should not require surgery.
Despite publicly providing a two-to-six-week timeline, the Colts realistically expect Luck to miss at least a month, league sources told ESPN's Ed Werder. The team has accepted the likelihood that Luck will be out longer than the minimum two-week projection, the sources told Werder.
The San Diego Chargers placed star wide receiver Keenan Allen on season-ending injured reserve last week with a lacerated kidney because they were told he wouldn't recover for at least six weeks and would not be cleared for contact even then.
Luck and Allen play different positions, and it is not known whether the severity of their injuries is the same, league sources told Werder.
Luck, according to Pagano, was injured when he scrambled on a second-and-9 play and took a hit from Denver linebacker Danny Trevathan in the fourth quarter of the Colts' victory over the Broncos on Sunday. Luck remained in the game and threw a touchdown pass to running back Ahmad Bradshaw on the next play. Despite the injury, it was arguably Luck's best game of the season, as he finished 21-of-36 for 252 yards, with two touchdowns and no interceptions.
Veteran Matt Hasselbeck will start at quarterback during Luck's absence. Hasselbeck, 40, won both of his starts earlier this season when Luck was out with a right shoulder injury. Hasselbeck is 48-of-76 for 495 yards and three touchdowns this season. The Colts, who lead the AFC South with a 4-5 record, have a bye this weekend and play at Atlanta on Nov. 22.
"We have all the confidence in the world, and obviously we're very fortunate to have Matt Hasselbeck as our backup quarterback," Pagano said. "We've won with Matt. We'll do the same thing, and certainly we will not put Andrew back out there again until he's 100 percent healthy."
The timing couldn't be worse for Indianapolis (4-5), which was hoping to return from this week's bye and build momentum with a favorable schedule. Instead, one week after firing offensive coordinator Pep Hamilton and replacing him with Rob Chudzinski, the Colts are now forced into making a quarterback change.
Indy took another precaution Tuesday by bringing former Monmouth quarterback Alex Tanney back to the practice squad. He spent three weeks in Indy earlier this season, none of it on the active roster. Luck, Hasselbeck and Tanney are the only quarterbacks on the team after Indy released former Wisconsin-Whitewater star Matt Blanchard from the practice squad Tuesday.
Playing behind a struggling offensive line has taken a toll on Luck this season.
He missed the first two games of his four-year career after getting hurt at Tennessee on Sept. 27. When Luck did return, he still didn't look right. Then last week, he was listed on the injury report with a bad ankle. He started, finished and won Sunday's game, looking more like the promising young quarterback whom people expected.
There has been speculation about possible fractured ribs and a more serious shoulder injury than the Colts first acknowledged.
"We will overcome this, and Andrew will make a full recovery and he will be back in the lineup at some point," Pagano said. "But we will overcome."
In the AFC South, the league's worst division, Indy holds a one-game lead over Houston.
Information from The Associated Press was used in this report.