Alex Ferguson's side have concentrated their firepower on bigger prizes since last lifting the FA Cup for a record 11th time in 2004 when they beat Millwall.
But knocking out the club who have won the FA Cup four times in the last six seasons - including the 2007 final when Chelsea beat United in the first final at the re-built Wembley Stadium - would be some consolation.
The clash at Old Trafford is the standout match of the quarter-finals which also features the all-Premier League tie between Everton and Wigan Athletic.
Manchester City, the 2011 winners, face 1912 winners Barnsley of the Championship and in an all-Championship tie Millwall meet Blackburn Rovers, who knocked out Arsenal in the last round.
"We've still got an FA Cup tie and we're still in a commanding position in the league. So we'll get over it, we'll bounce back," United assistant manager Mike Phelan told the club's website after United's 2-1 home defeat by Real Madrid in which Nani was controversially sent off.
"We've had disappointments before and we'll get over this one. We'll come in (to training) and kick on.
"The players will rally round, the staff will rally round and we'll be Manchester United right the way through until the end of May."
Chelsea perhaps have a different emphasis with finishing in the top four of the Premier League and ensuring Champions League qualification the priority although a Cup quarter-final at Old Trafford will focus minds.
Chelsea's interim manager Rafael Benitez caused a storm last week when he confirmed he was leaving in May and took a swipe at the board and the club's fans who continue to boo him with the Londoners sitting a perilous fourth in the Premier League table.
However, the Spaniard will relish trying to get one over Ferguson, who he often locked horns with during his time at Liverpool.
Benitez only faced Ferguson once in the FA Cup, masterminding a 1-0 fifth-round victory in 2006 when Liverpool went on to lift the trophy.
Considering they trail United by 12 points in the title race, champions Manchester City's best hope of salvaging silverware from a disappointing season is the FA Cup and a home game against Barnsley should represent a comfortable route into the semi-finals.
City midfielder Javi Garcia still believes they can overhaul United but for now the priority is avoiding any shocks against Barnsley, who are a mystery to the Spaniard.
"We are only thinking of our FA Cup tie with Barnsley," he said. "I know nothing about them if I'm totally honest, but this week the boss and his backroom staff will give us the run-down on how they play.
"We certainly don't expect anything less than a tough 90 minutes."
Barnsley, who played a competition record 12 matches when they lifted the Cup for the only time in their history 101 years ago, last made an impact in the competition when they lost to Cardiff City in the 2008 semi-finals having beaten Liverpool and Chelsea along the way.
They are managed by David Flitcroft, brother of former City player Garry, and David said the south Yorkshire club, who are in danger of sliding into the third division, have taken inspiration from fourth tier Bradford City's run to the Capital One (League) Cup final.
"I have been inspired by Bradford and I am trying to make new heroes at this club," he told the BBC.
Everton still have painful memories of a semi-final defeat by Liverpool at Wembley last season, although defender Seamus Coleman said that setback has provided the perfect motivation against a Wigan side preoccupied with their annual battle to stay among the Premier League elite.
"Hopefully we can get past Wigan on Saturday to get back there (to Wembley) for the fans and make it a good year," he told Everton's website.
"But we have to be professional about it.
"Anything can happen in the cups - look at Bradford in the League Cup knocking big teams out."
Wigan have reached the quarter-finals for the first time, and their owner Dave Whelan would like nothing better than seeing his side at Wembley, where, he says, he has unfinished business.
Whelan broke his leg in the 1960 final playing for Blackburn against Wolverhampton Wanderers who went on to win the cup 3-0.
Whelan told Sky TV: "It still brings a tear to my eye. You never get over something like that, it was a sad day for me and for Blackburn and I would like nothing better to go back and wn the cup with Wigan now."
Blackburn manager Michael Appleton has enjoyed a remarkable journey to the quarter-finals.
He began the competition in charge of Portsmouth, then took over at Blackpool, holding Fulham to a replay, and after moving to Blackburn claimed the scalp of Arsenal in the fifth round.