They'll try to avoid their first 0-5 start since 1997 on Sunday when they host the Kansas City Chiefs, who are coming off their first win.
Indianapolis (0-4) is among four teams still searching for their first victory, a position that wasn't difficult to foresee after it was learned Manning could miss the season following neck surgery.
The Colts have struggled to replace him. Kerry Collins started the first three games, posting a 65.9 passer rating, and Curtis Painter was under center for Monday's 24-17 loss at Tampa Bay with Collins suffering from concussion-like symptoms.
Coach Jim Caldwell wouldn't reveal his plans for Sunday if Collins is cleared to play. Painter completed 13 of 30 passes for 281 yards and two touchdowns Monday, but he struggled in the fourth quarter, going 4 of 10 for 56 yards while getting sacked three times as the Buccaneers went ahead.
"He did the things we asked him to do," Caldwell said. "He had some bright spots, but we'll see how things go in the next day or so."
Quarterback isn't the only position Caldwell is concerned about after the Colts lost several more players to an already crowded injury list.
Defensive tackle Eric Foster suffered a partial dislocation of his right ankle, ending his season, while rookie Drake Nevis left with an undisclosed injury. Defensive captain Gary Brackett and starting safety Melvin Bullitt were already out for the year.
The new injuries further weaken a defense that ranks 25th in yards allowed (390.3 per game). The Buccaneers finished with 466 yards, including 192 on the ground.
"I think overall we can play better," Caldwell said of the defense. "They got a couple of big (passes) against us, and then in terms of our tackling as well, we weren't as good at getting guys down as we were the week before."
Indianapolis also suffered some big losses on the offensive line. Rookie first-round pick Anthony Castonzo left Monday's game with an ankle injury that is likely to keep him out Sunday, and backup Ben Ijalana suffered a torn ACL. Veteran Ryan Diem was already out with a sprained ankle.
With their season rapidly falling apart, the Colts are looking elsewhere to improve their depth, signing tackles Michael Toudouze and Quinn Ojinnaka to the active roster and elevating defensive tackle Ricardo Mathews from the practice squad.
One more loss would give the Colts their first 0-5 start since 1997, when Manning was still a student at Tennessee. They're already in the midst of their longest losing streak since a five-game skid in 2001.
Kansas City (1-3) doesn't have much sympathy as it tries to build off last Sunday's 22-17 victory over winless Minnesota.
Inundated with key season-ending injuries of their own - most notably to Jamaal Charles, Eric Berry and Tony Moeaki - the defending AFC West champion Chiefs had their own rough start. They dropped their first two games by a combined score of 89-10 before their upset bid at San Diego came up just short in Week 3.
Since losing Charles, Kansas City has struggled to find consistency in the ground game, with veteran Thomas Jones averaging just 2.8 yards per carry. The Chiefs are averaging 110.8 rushing yards per game, a steep decline from the league-leading 164.2 they had last year.
Kansas City is hoping to have better success rushing the ball against the Colts' struggling run defense, which ranks 28th in the league (133.0 yards per game).
"We got a tough, resilient bunch of guys that care, and that's really important," coach Todd Haley said. "They fight and they're going to fight to win, and to be a good team, and I believe that we will be that. We just have to make sure we're getting better every game."
The Chiefs have lost 10 of 11 to the Colts - including three playoff games - dating back to 1990. Indianapolis won 19-9 last October in a game that had seven field goals and one touchdown.