Roberto Mancini's side go into the game at Eastlands on the back of two defeats in the space of four days, a run that has raised questions about whether they will last the course this season.
They were beaten 1-0 in Lisbon on Thursday, with captain Vincent Kompany limping out in the early stages in Portugal.
Then came another damaging loss by the same score-line at Swansea on Sunday, which saw City lose top spot in the Premier League for the first time since October.
They now trail United by a point in the Premier League with 10 matches remaining and after facing Sporting on Thursday, they host Chelsea the following Wednesday.
By then they could be four points behind the champions, who head to struggling Wolves on Sunday.
The domestic title is undoubtedly City's priority.
But with six days before they face Chelsea, due to the London club's participation in the FA Cup, Mancini is likely to go with a strong selection as City look to wipe out the advantage gained by Xandao's goal in Portugal last week.
City's failure to score in successive matches for just the second time this season has sparked a clamour for Carlos Tevez to be recalled to Mancini's squad for the run-in.
The Argentina striker, 28, has played in two reserve matches since returning from three months in his homeland without permission.
But he was not included in the Europa League squad submitted by Mancini in January and will have to wait until next week's home game against Chelsea for his first senior appearance since September.
City's defeats are just the second time they have experienced back-to-back losses since October 2010 but defender Micah Richards is sure that they will put their recent problems behind them.
"We have to take every game as it comes. We need to go back and see where we went wrong and why we are not scoring as many goals as we used to," Richards said.
"Teams are defending better against us. At the start of the season we were scoring, four, five or six goals a game but in the last two games we have not hit the net and it is something we want to look at and improve on in next couple of games."
City were frustrated that their first-ever Champions League campaign ended at the group stages.
But although the Europa League is widely-derided, Mancini will be keen for City to progress.
The Italian ended a 35-year trophy drought when he guided City to the FA Cup last season and knows that supporters are desperate to get as much silverware as possible despite the importance of fighting off neighbours United in the Premier League.
They will still be confident that they can pull the tie back, having won all of their 14 Premier League home matches, as well as winning three of their four home matches in Europe this season.
Joleon Lescott is doubtful for the last 16 second leg with a groin problem sustained in Wales on Sunday.
Kompany is likely to target the Chelsea match for his return from a calf injury sustained in Lisbon, while Pablo Zabaleta is also out with a thigh strain.
Sporting followed up their win over City with a 5-0 victory over Vitoria de Guimaraes on Sunday but Carlos Freitas's team remains fourth in the Portuguese league.