With a 3-1 lead over Belgian outfit Brugge, the Reds will look to finish the job on the road in the second leg and seal a place in Friday's group stage draw.
It gives the Reds a good advantage, although the Belgians have a crucial away goal and need a 2-0 win to secure qualification to the group stages if United failed to score.
The loser of this play-off tie will drop into the UEFA Europa League whilst the winner will be one of 32 sides in the hat for the group stages (United would be in Pot 2 if we qualify).
Bastian Schweinsteiger made his first start of the season in Saturday's draw with Newcastle and played for 60 minutes, although it is unclear whether the German will keep his place in the XI over Michael Carrick.
United's two Belgium internationals Adnan Januzaj and Marouane Fellaini are set to feature against their homeland.
Phil Jones is still recovering from a mild case of thrombosis and Marcos Rojo is continuing to improve his match fitness.
Brugge are expected to be without their captain Timmy Simons through injury, and Brandon Mechele is definitely out through suspension following his sending off at Old Trafford.
United manager Louis van Gaal said:
"It is a difficult ground, I know this from before and I know that it is not a simple opponent.
"I have read in the papers that it shall be simple and a walkover, but it isn't like that.
"Brugge against Panathinaikos, a strong team in this competition, they won 3-0 in the previous round.
"It is still a game, but because of our situation and our third goal we have more confidence.
"We have to be careful, we have the quality to win but we shall need to be ready."
Form guide: Brugge W D W L L United W W W D
Match odds: Brugge 10/11 Draw 13/7 United 13/4 (Marathonbet)
Referee: Antonio Mateu Lahoz (Spain)