Middle linebacker Jevohn Miller, the team's leading tackler, was the latest to go down. Miller injured a knee on the second play of Saturday's 59-14 loss to Oklahoma and was undergoing an MRI Monday to determine the extent of the damage.
If Miller is lost for the rest of the year, which seems likely, it would be the ninth season-ending injury for the Cyclones (2-6, 0-5 Big 12), a series of misfortune that started on the first day of practice, when offensive lineman Ben Loth tore an ACL.
''It just weighs on you,'' center Tom Farniok said. ''It's annoying. But it's part of football. You have to adjust.''
Before Miller got hurt, the most damaging injury had been to wide receiver Quenton Bundrage, the Cyclones' top deep threat. Bundrage tore an ACL on the fourth play of a season-opening loss to North Dakota State.
Knee injuries also have sidelined two other wide receivers, P.J. Harris and Brett Medders. The others lost for the season are offensive linemen Brock Dagel and Jacob Dunning and special teams players Levi Peters and Matt Swoyer.
All had knee injuries except Peters, who tore his Achilles tendon.
With their long list of ACL injuries, the Cyclones have been left wondering: Why us?
''You can attribute that to a million different things,'' Farniok said. ''It's fluke. You get hit just right, it's a roll of the dice. You could have 12 knee injuries in a year, you can have none. It's the kind of luck you get sometimes.''
Miller's injury robbed a defense that already was struggling of its leader. He was hurt when blocked as Oklahoma quarterback Trevor Knight turned a bad snap into a 31-yard touchdown run.
''It's ugly on tape, I know that,'' Iowa State coach Paul Rhoads said. ''It's a clean play. It's a legal block. I've got no problem with what happened on the play. (It was) a bad result of a botched snap that caught his eyes and his eyes didn't go to where they should have been to help defeat the block.''
Cornerback Nigel Tribune missed that game because of a groin injury and defensive lineman Devlyn Cousin sat out because of an elbow injury. Another defensive lineman, Brandon Jensen, has been hampered by a knee injury and left the game after the first series. Defensive tackle Robby Garcia also missed the game.
Weakened in the middle, the Cyclones allowed 510 yards rushing.
''You've got three of your top four defensive tackles who were out Saturday, going up against an offensive line (that) averaged about 335 pounds, they get after you,'' Rhoads said. ''Then you lose the Big 12's third or fourth leading tackler who's right in the middle and you're playing without arguably your best cornerback in Nigel, it's got a big effect on the outcome of a game and how well your team plays and how accurately you get lined up.''
While wide receiver is Iowa State's deepest position, losing Bundrage still was a major blow because of his big-play capabilities. Bundrage tied the school record with nine touchdown catches last year and three went for more than 60 yards, including a 97-yarder against Texas.
The Cyclones would have needed just one play like that in narrow losses to Kansas State (32-28) and Texas (48-45) to possibly reverse those outcomes, which would have turned 2-6 into 4-4.
''With football, injuries are common,'' defensive lineman Corey Morrissey said. ''But with the injuries we've had, guys leading the team, it's crucial parts who are getting injured out there. Everything just stacks up.''