All three need to win next week's first knockout round, second legs to reach the quarter-finals after Chelsea lost 2-1 at Barcelona, United 1-0 at home to AC Milan and Arsenal 3-1 at Bayern Munich.
Liverpool were the only winners, beating Bayer Leverkusen 3-1 at Anfield, but they must bridge an eight-point gap on Merseyside rivals Everton to earn a place in next season's Champions League qualifiers.
Europe is also in the spotlight further down the table after Chelsea's League Cup final victory over Liverpool.
With Jose Mourinho's men destined for the Champions League, the UEFA Cup slot normally taken by the Cup winners will revert to the sixth-place finishers in the league -- a position to which Middlesbrough, Bolton Wanderers, Tottenham Hotspur and Charlton Athletic can all aspire.
For the big clubs, the name of the game this weekend will be to get maximum points from the minimum number of first-team regulars.
Sporting glory and huge financial windfalls have made the Champions League the number one priority and teams involved are unlikely to use players who are tired or not fully fit.
The fixture list has, however, given the three top sides a helping hand. Chelsea take on a Norwich City team heading for a swift return to the second division and Manchester United play Crystal Palace, who are just one place above the drop zone.
Victory for United would leave Chelsea with only a three-point lead at the top when they begin their game at Carrow Road, though Mourinho's men would have two matches in hand.
Arsenal, despite being hit hard by injuries and suspensions, host struggling Portsmouth, who have lost six of their last seven league games.
Only Liverpool, buoyed by their first-leg lead to take to Germany, have a difficult game in prospect when they travel to St James' Park to face Newcastle United.
Manager Rafael Benitez will expect his side to shake off the disappointment of their defeat in Cardiff as they look to keep the pressure on Everton, who have a much easier looking game at home to Blackburn Rovers.
Tipped for relegation at the start of the season, Everton could be playing in the next Champions League and, with confidence high after last weekend's impressive win at Aston Villa, are likely to give Mark Hughes's men a torrid time.
