Rooney, whose knee injury prevented him from making the trip to the Black Country, was sorely missed by the champions against a vibrant Wolverhampton Wanderers team.
But Scholes came to United's rescue with a 73rd minute winner that lifted Sir Alex Ferguson's team to the top of the Premier League and registered his 100th top flight goal for the club.
The 35-year-old, out of contract in the summer, has scored more spectacular goals, but the manner in which he calmly controlled Jody Craddock's mis-clearance before shooting past goalkeeper Marcus Hahnemann underlined his enduring class.
Having won just once in nine league games prior to United's visit to Molineux, Wolves had slid to the brink of the relegation zone, raising the spectre of return to the Championship after just one season in the top flight.
So with their position growing increasingly precarious, it was perhaps no surprise that manager Mick McCarthy chose to field his strongest available team against the champions.
Three months ago, McCarthy earned widespread condemnation, and a suspended fine of £25,000 for his club, by resting a host of key players for the corresponding fixture at Old Trafford, which United won 3-0.
Wolves cannot pick and choose their games at this stage of the season, however. Every point counts and, having claimed a 1-0 victory against United on their last league encounter at Molineux in January 2004, why couldn'tthey do again?
United, without the injured Wayne Rooney and Michael Owen, were certainly less formidable than they might have been and the absence of Rooney in particular appeared to lift the home team.
Midfielder Matt Jarvis and Irish forward Kevin Doyle proved a thorn in United's side in the first-half and Wolves should have taken the lead. Doyle went close as early as the fifth minute, when Jarvis had beaten right-back Wes Brown before pulling back for the former Reading forward, who scuffed a left-foot shot wide from 12 yards.
United were slow to respond and they only threatened the Wolves goal when Darron Gibson sliced a shot wide from close range after Nani's free-kick had struck an old gold wall.
The champions were strangely uncertain. With Rio Ferdinand and Nemanja Vidic reunited in the centre of defence for the first time since the 2-0 defeat at Liverpool on Oct 25, Doyle would not have expected to enjoy such freedom as the lone striker.
But he was given the time and space to tee up David Jones, following another delivery from Jarvis, on the half hour before Jones saw his deflected shot saved.
Wolves were rising in confidence and their best opportunity came moments later when Jarvis made easy work of Brown again before delivering a dangerous cross to the far post.
Full-back Stephen Ward found himself with a golden opportunity to score, but his header from inside the six-yard box was brilliantly saved by Edwin van der Sar.
Without Rooney, Owen and Ryan Giggs, whose broken arm will continue to sideline him when AC Milan visit Old Trafford on Wednesday, United lacked threat and Wolves were doing their best to take full advantage.
With Brown being forced out of the action with a knee injury at half-time, Ferguson was forced to introduce Gary Neville at the interval. Despite the club captain's vast experience, Neville's lack of pace against Jarvis would have been a concern for the United manager.
Yet Neville's presence worked in United's favour as the 34-year-old closed the space on Jarvis and bolstered the support for Antonio Valencia down the right flank.
Having been stretched by Wolves in the first-half, United were now compressing the space and rolling the home side back towards their own penalty area.
But for a 47th minute block by Christophe Berra, Dimitar Berbatov would surely have opened the scoring for United and Patrice Evra also went close with a left-foot effort five minutes later.
Neville's defensive frailties surfaced on 68 minutes, however, when former Gillingham winger Jarvis burst to the byline before delivering another dangerous cross that Wolves failed to take advantage of.
Wolves had now carved open the United defence on numerous occasions, but failed to capitalise every time and, against teams of the calibre of United, there is usually a price to pay for such profligacy.
And so it proved for McCarthy's team when Scholes claimed his sixth goal of the season by calmly beating Hahnemann on 73 minutes.
If only he was 10 years younger, Ferguson would not have to worry about Rooney missing the odd game here and there.
But United cannot rely on their veterans to pull them out of the mire forever.
Paul Scholes is the 19th player to score 100 Premier League goals. It took him 436 matches. Only Ryan Giggs reached the milestone in more games.
Number of gamesAlan Shearer 124Thierry Henry160Ian Wright173Robbie Fowler175Les Ferdinand175Andrew Cole185Michael Owen185Jimmy Floyd Hasselbaink200Wayne Rooney247Dwight Yorke254Teddy Sheringham254Matthew Le Tissier 254Robbie Keane 255Nicolas Anelka 258Dion Dublin 271Emile Heskey407Frank Lampard414Paul Scholes436Ryan Giggs 534