The team officially ruled out wide receiver Hakeem Nicks (broken toe) and center Shaun O'Hara (ankle/Achilles) on Friday. Starting cornerback Corey Webster is also questionable with rib and knee injuries.
The Giants need a win in Washington and need the Bears to beat the Packers to qualify for the postseason.
They have been hampered by injuries at wide receiver and on the offensive line all season; they'll likely start their seventh different combination on the offensive line on Sunday. They've started five different combinations at wide receiver.
"We've had to do it before and we've shown the capacity to adjust," offensive coordinator Kevin Gilbride said. "The guys have stepped up and done what we needed to do to get a win, so we certainly look forward to them doing the same thing this week."
O'Hara aggravated a left ankle and left Achilles injury last week against Green Bay. He has played in just six games this season due to various injuries. He said on Thursday that he may need offseason surgery to "clean out" his ankle injury.
Rich Seubert will likely replace O'Hara at center. Seubert has started six games at center this season for the Giants. Left tackle David Diehl said on Thursday that he'd been practicing at left guard. If he plays there on Sunday, look for backup offensive lineman Shawn Andrews to play left tackle.
Andrews sat out three games with a back injury earlier this season. The former Philadelphia Eagle has had surgery twice on his back and said Friday that he will need a shot of the pain-killer torodol before playing on Sunday.
"The back has been feeling pretty good," Andrews said. "I'm just doing what I need to do to make sure that I can sustain for the length of the game."
"I have to time it right [the injection]," Andrews said. "I think two weeks ago I got the shot right before we went out for the kickoff [against Philadelphia on Dec. 19] and it didn't kick in until I got home," he said, laughing.
"I'm serious, man. I'm sitting there on the couch and feeling good," he added. "Now I get it as soon as I go over there, right when I get there so it can kick in and resonate throughout my body."
Besides the shots, Andrews has had three treatments provided with an epidural injection. He also was hospitalized in late November because the back pain was so severe against Philadelphia on Nov. 21. He missed the next three games and has seen limited action in the last two.
While he knows having to take shots before games can't be good for his body long term, Andrews says he takes them because he is "living in the now."
"Me and my body are talking it out right now," Andrews said. "We're seeing where we are. We're seeing right now we have the Redskins and that's where we are."
Derek Hagan, who had a season-high seven catches for 64 yards against the Redskins in Week 12, will likely start in place of Nicks, who broke his toe in the Giants' 45-17 loss to Green Bay last week.
If recent history is any indication, Nicks' absence may hurt the Giants more that O'Hara's.
The Giants ran the ball for 410 yards in their most-recent two-week stretch without O'Hara. They have run for 190 yards in the last two weeks with O'Hara back at center.
Nicks , however, has clearly established himself as Eli Manning's top target this season, particularly after Steve Smith was lost for the season with a knee injury. The second-year wideout leads the Giants with 79 catches and 1,052 receiving yards. He also has 11 touchdowns.
Manning noted that the Giants executed well in the two games they've played without both Nicks and Smith -- wins over Jacksonville and Washington.
"We've got to execute," said Manning, who has thrown an NFL-high 24 interceptions this season. "That's what it comes down to. Can you execute? Can you have a great game plan where guys know what's going on, where to line up, run routes and play good football?"
As for Webster, the sixth-year corner sat out of practice all week with knee and rib injuries. He's optimistic about playing on Sunday and noted that he played against the Eagles in Week 10 despite missing nearly all of practice in the week leading up to the game. Webster said that he's played through the pain associated with the rib injury for the past few weeks.
"If I don't think I can help the team and play like I normally play, then I don't want to be out there; I don't want to hurt the team," said Webster, who wears extra padding to protect his ribs. "But if I can go, then I'm definitely going to try to be out there."
The Giants have also ruled out defensive lineman and special teams contributor Dave Tollefson due to an MCL injury.
Ian Begley is a regular contributor to ESPNNewYork.com. Information from The Associated Press was used in this report.