This is a historic first meeting in European competition between English football's two most successful clubs and United manager Louis van Gaal is relishing a "fantastic occasion".
Van Gaal will become the first Reds boss to win five consecutive matches against the Merseyside men with victory on Thursday, but Liverpool are building a run of promising form under Jurgen Klopp and will look to take an advantage into next week's Old Trafford return.
The hosts come into this one off the back of three successive league wins- coupled with a penalty shootout defeat to City in the League Cup final- in what is sure to be a cauldron of noise for this first leg tie at Anfield.
Jesse Lingard is suspended after picking up a booking in the last round against Midtjylland, but Antonio Valencia could be on the bench with Bastian Schweinsteiger also not far away from a return.
Adnan Januzaj and Tim Fosu-Mensah are both ineligible, with Phil Jones, Ashley Young, Luke Shaw and Wayne Rooney all still out for United.
With both sides adrift of the Premier League pacesetters- and a Champions League spot up for grabs for the winner- the Europa League still remains the most likely route back to Europe's top table for both these sides, whom share eight European Cups between them.
"It is always a big game traditionally and historically, for the fans as well, especially because both sides are fighting for the Champions League so it is a very important match" said Van Gaal.
"It shall be a fantastic occasion, we have to win- it is a cup competition but it is no different because we want to win a trophy.
"The fans of Manchester United are appreciating playing the Europa League, we shall have 75,000 fans at Old Trafford (for the second leg) and Anfield is sold out also, so it's very important and everyone is looking forward to these games" added the Dutchman.
Liverpool have won the UEFA Cup- the precursor to the Europa League- three times, most recently in 2001 whilst United are looking to go all the way for the first time having reached the last eight in 1985.
Liverpool narrowly edged out Klopp's countrymen Augsburg in the last round (1-0 on aggregate) and United saw off Danish champions Midtjylland 5-1 at home for a 6-3 overall success.
Form guide: Liverpool W D W D W W United L W W W W L
Match odds: Liverpool 11/10 Draw 5/1 United 10/5
Referee: Carlos Velasco Carballo (Spain)