Winger Ashley Young put three-times European champions United ahead just before the hour mark and Javier Hernandez extended the lead five minutes from time as they showed they meant business in a competition they would rather not be in.
Their domestic title rivals Manchester City made it harder for themselves in Portugal by conceding in the first half against the run of play before an Alvaro Pereira own goal and a late Sergio Aguero strike put them on course for the next round.
Other teams to build a solid advantage ahead of next week's second legs were Ukrainian side Metalist Kharkiv who won 4-0 at Salzburg and Atletico Madrid who take back to Spain a 3-1 win over Lazio after fighting back from a goal down.
The 2004 winners of the UEFA Cup - the Europa League's predecessor - Valencia secured a 1-0 win at Stoke City to sit pretty halfway through the tie while Twente Enschede came away with the same scoreline from Steaua Bucharest on a cold night.
Schalke 04 were glad to grab an equaliser 15 minutes from time to draw 1-1 at Viktoria Plzen, while Legia Warsaw's tie with Sporting was also evenly balanced after a 2-2 draw in Poland and Udinese and PAOK Salonika played out a 0-0 draw.
German side Hannover 96 needed an 80th-minute penalty by Jan Schlaudraff to complete a comeback at home to Club Bruges who had taken the lead early in the second half through Maxime Lestienne before Arthur Sobiech's equaliser.
In the day's other games, AZ Alkmaar beat Anderlecht 1-0 courtesy of Adam Maher's 35th-minute goal, Lokomotiv Moscow came from behind to overcome Athletic Bilbao 2-1 and PSV Eindhoven held on to an early two-goal lead to win 2-1 at Trabzonspor.
The English champions picked up the pace after the break and made the breakthrough when Nani's cross eventually found Young in space and the
