Robin van Persie will return to Old Trafford after Manchester United were drawn in a Europa League group with Fenerbahce.
United were drawn in Group A alongside Fenerbahce, Feyenoord and Zorya Luhansk.
European debutants Zorya Luhansk – who reached the play-offs in the last two years but failed to progress – are based in the east of Ukraine, close to the border with Russia.
However, because of the war in that part of the country Jose Mourinho’s side are set to play at the Slavutych Arena in Zaporizhia, which is more centrally located.
Southampton have a glamour tie against Inter Milan and have also been drawn against Sparta Prague and Israel’s Hapoel Be’er Sheva, who gave Celtic a scare in their Champions League qualifier.
League of Ireland side Dundalk also have to go to Israel to face Maccabi Tel-Aviv with Zenit St Petersburg and AZ Alkmaar their other opponents.
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Mourinho seemed happy enough to have the chance to face different opponents.
“There are groups in the Champions League that are very similar, so it is good for that,” he told a press conference.
“We all know the competition is not the same as the Champions League but to have Manchester United playing against clubs with tradition like Fenerbahce and Feyenoord is good for us.
“I don’t have more vision about Ukraine. We know that it will be a difficult group, but I think that is a good thing. If you have teams without expression then even the fans may not enjoy Thursday nights at Old Trafford.
“It is good for the fans and for the players because it will help motivation.”
Southampton’s executive director of football Les Reed said they were relishing matches against some of Europe’s historic clubs.
“It’s a very exciting draw for everyone involved at the football club,” he told saintsfc.co.uk.
“There are some big challenges for us, with a big giant in Inter Milan. I’m sure everyone will look forward to that home and away, but the other two games will also be great tests for us with excellent atmospheres.”