Polamalu sprained a knee and Holmes injured ankle ligaments during a 19-16 overtime loss Sunday, one of the NFL's biggest upsets this season. Both are listed as doubtful for Monday night's home game against Miami (0-10).
Although coach Mike Tomlin wouldn't list either player as out, he talked Tuesday as if neither would play. Both injuries are the type that can sideline players for multiple games.
Tomlin called them "two significant injuries."
Holmes has a sprain in his upper right ankle, or injured ligaments between the two major bones of the lower leg at ankle level. While Holmes' sprain is mild, the injury is typically much worse than a regular sprain and can keep a player out for three to four weeks.
Holmes' absence would be a major setback to an offense that managed only one touchdown and 151 yards passing against the Jets (2-8), who had previously won only one game. It also takes away quarterback Ben Roethlisberger's top deep threat.
Holmes, a first-round draft pick in 2006, leads the division-leading Steelers (7-3) in receptions (39), touchdown catches (7) and average gain per catch (17 yards).
Tomlin wouldn't choose a replacement starter for Holmes, saying Nate Washington, Cedrick Wilson and possibly Willie Reid would divide playing time. Washington had two TD catches Nov. 5 against Baltimore and is the only Steelers wide receiver other than starters Holmes and Hines Ward with a touchdown reception.
"It's going to require multiple people to step up and fill the roles they provide for us, which is great," Tomlin said. "This is a team, and it's the ultimate team game. We're looking forward to these guys stepping up and delivering for us."
The Steelers have been relatively injury free most of the season, but are currently without both starting safeties. Free safety Ryan Clark (spleen) went on injured reserve last week, with Anthony Smith starting the last four games in his place.
While Polamalu is having a down season statistically, with no interceptions or sacks and one fumble recovery, his ability to shift positions from play to play is an important element of Pittsburgh's league-leading defense.
Opposing coaches talk constantly of adjusting to Polamalu, who may line up as a pass-rushing linebacker on one play or in deep zone coverage on the next. Despite Sunday's loss, the Steelers are allowing an average of 40 fewer yards per game than any other team.