City's hopes of reaching the Champions League quarter-finals for the first time were dealt a sizeable blow on Tuesday when they fell to a 2-1 loss at home to Barcelona in the first leg of their last 16 tie.
The result seriously compromises their chances of going through and the extent of Barcelona's first-half dominance will take some forgetting, but Sunday's return to domestic duties promises much.
With leaders Chelsea not in action due to their participation in Sunday's League Cup final against Tottenham Hotspur, a City win at Anfield will lift the defending champions to within two points of the summit.
City then face a kind run of fixtures, against Leicester City, Burnley, West Bromwich Albion and Crystal Palace, at a time when Chelsea, held to a 1-1 draw by Burnley last weekend, have begun to show frailties.
Victory at Liverpool, the team City pipped to last season's title, will not be straightforward, with Brendan Rodgers's side unbeaten at home since November and on a 10-game unbeaten run in the league.
But Rodgers feels that Liverpool's draining trip to Istanbul on Thursday, where they lost on penalties following extra-time to Besiktas in the Europa League, could give City an advantage.
"That extra period of 48 hours that City have could be crucial, certainly physically, especially as we will have very little preparation time," Rodgers said.
"But the players have had lots of challenges to overcome this season and we are ready to keep performing and doing the best we can."
Liverpool, currently sixth, will recall Brazilian playmaker Philippe Coutinho after he was rested for the trip to Turkey, while Yaya Toure returns for City after missing the Barcelona defeat through suspension.
Another side bidding to overcome European disappointment are Arsenal, who host Everton on Sunday, four days after a demoralising 3-1 home defeat by Monaco in the Champions League.
A run of seven wins in nine games had seen Arsene Wenger's side climb to third place in the league table, but with their Champions League hopes now hanging by a thread, the club have been plunged into doubt.
- United seek reaction -
"It was a hugely disappointing night, you could feel that after the game in the stands and in the dressing room, but there is still a small chance (to qualify)," said German centre-back Per Mertesacker.
"We still have hope to come back even stronger from that disappointment."
With just four points separating third-place Arsenal and seventh-place Tottenham, the battle for Champions League qualification is one of the fiercest for several seasons.
Southampton, a point below the top four in fifth place, visit West Bromwich Albion, where they will look to re-energise their season following a return of just one win in four matches.
Manchester United, a point better off in fourth place, are also hoping to return to winning ways after seeing a seven-game unbeaten run ended by a 2-1 loss at Swansea City in their last outing.
Louis van Gaal's side welcome Sunderland to Old Trafford on Saturday and centre-back Phil Jones says United's players are itching to get back onto the pitch.
"It's an important game for us," he told the United website
"It won't be easy
Sunderland are a tough team, but we've done well at home recently and we need to bounce back from the defeat at the weekend."
In the battle to avoid relegation, third-bottom Burnley host Swansea, while Tim Sherwood goes in search of his first points as manager of second-bottom Aston Villa when his new side visit Newcastle United.
An injury-time Victor Moses penalty saw Villa fall to a 2-1 home defeat by Stoke City in Sherwood's first game in charge, but he believes six wins from their final 12 games will be enough to secure survival.
"The reality has to kick in that we're in a dogfight here and we need points as soon as possible," he said.
"They've won five games of football all season and we need to win six to stay in the division with not many games left."
Fixtures
Saturday (1500 GMT unless otherwise stated):
Burnley v Swansea City, Manchester United v Sunderland, Newcastle United v Aston Villa, Stoke City v Hull City, West Ham United v Crystal Palace (1245 GMT), West Bromwich Albion v Southampton
Sunday:
Arsenal v Everton (1405 GMT), Liverpool v Manchester City (1200 GMT)
Source : AFP
Source: AFP