United blew away a 10-man Athletic Bilbao in Spain 3-0 on Thursday while Tottenham took a big step towards salvaging a poor domestic campaign with a 3-1 home win against Bodo/Glimt.
Brennan Johnson struck after only 38 seconds to appease an expectant home crowd before James Maddison fired a second for Ange Postecoglou's men in the 34th minute.
A third followed through Dominic Solanke from the penalty spot after 61 minutes as Spurs put their poor Premier League form to one side to produce another stirring display in Europe.
Bodo had penalty appeals waved away just before the half hour mark after Isak Dybvik Maatta went down softly with Rodrigo Bentancur and Destiny Udogie in close proximity.
Given Bodo's ominous home form, Postecoglou urged Tottenham to keep playing and Udogie had a shot saved before a Dejan Kulusevski effort was deflected wide.
Spurs were then hit with a sucker-punch as Bodo captain Ulrik Saltnes reduced the deficit in the 83rd minute when he worked a yard of space and had a shot deflected off Bentancur.
Meanwhile United produced possibly their finest performance of the season to take a commanding first-leg lead against Bilbao.
Carlos Casemiro headed Ruben Amorim's team in front in the 30th minute after a cross from Harry Maguire.
It was 2-0 seven minutes later when Rasmus Hojlund was brought down in the box by Dani Vivian and a penalty was awarded after a VAR review.
Vivian was shown a red card for the foul and Bruno Fernandes converted from the spot.
Fernandes got his second and United's third in the 45th by running through on goal and curling a shot past goalkeeper Julen Agirrezabala.
United's win could have been even more emphatic with Noussair Mazraoui and Casemiro both hitting the woodwork.
The second leg is at Old Trafford next Thursday and United is potentially just 90 minutes away from returning to Bilbao, which is staging the final on May 21.
Spurs are on the road for their second leg next week, with their Norwegian opponents proving tough to beat on their home turf.
United have won the Europa League once, in 2017, while Tottenham have won the trophy twice when the competition was known as UEFA Cup.
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