While many expected the demotion to Europe's second tier would be a blow to the Manchester pair's prestige, both fixtures would not be out of place in the Champions League knockout phase.
Porto, who secured the trophy last year under the guidance of now Chelsea boss Andre Villas-Boas, host City in the first leg before a return fixture at the Etihad Stadium, while United will play in the Amsterdam ArenA first.
Stoke City completed a trio of difficult assignments for English sides when they were drawn against Valencia.
In the draw for the last 16, United discovered they will face one of Lokomotiv Moscow or Athletico Bilbao if they get through. City will take on either Legia or Sporting if they see off Porto and a victory over Valencia would see Stoke play either Trabzonspor or PSV Eindhoven.
Stoke manager Tony Pulis said: "It's a great draw for us. Valencia are one of the top teams in Europe with great traditions in the European competitions.
"I was desperately hoping that we would get a draw against a big club where our supporters wouldn't have to travel too far because they have been looking forward to an opportunity such as this one where they can go to the away leg.
"They will be delighted. They can all have a great Christmas and then they've got eight weeks to save up for the trip to Spain. It would be fantastic if we could take a large army of fans over there and show them what this football club is all about."
EUROPA LEAGUE LAST 32 DRAW
Porto v Manchester City
Ajax v Manchester United
Lokomotiv Moscow v Athletic Bilbao
Salzburg v Metalist Kharkiv
Stoke City v Valencia
Rubin Kazan v Olympiacos
AZ Alkmaar v Anderlecht
Lazio v Atletico Madrid
Steaua Bucharest v Twente
Viktoria Plzen v Schalke
Wisla Krakow v Standard Liege
Braga v Besiktas
Udinese v PAOK
Trabzonspor v PSV Eindhoven
Hannover v Brugge
Legia Warsaw v Sporting
* First legs to be played February 16, second legs February 23
EUROPA LEAGUE LAST 16 DRAW
FC Salzburg/Metalist v Rubin Kazan/Olympiacos
Legia/Sporting v Porto/Manchester City
Steaua/Twente v Viktoria Plzen/Schalke
Wisla/Standard Liege v Hannover/Brugge
Stoke/Valencia v Trabzonspor/PSV Eindhoven
Alkmaar/Anderlecht v Udinese/PAOK
Lazio/Atletico Madrid v Braga/Besiktas
Ajax/Manchester United v Lokomotiv Moscow/Athletic Bilbao
* First legs to be played March 8, second legs March 15.