The first leg will be played at the Olimp2 stadium - a round trip of nearly 4,000 miles - on Thursday 9 March with the return meeting at Old Trafford a week later.
Sandwiched between the two matches is the FA Cup quarter final at Chelsea, scheduled for Monday 13 March with Middlesbrough at home in the league on the 19th.
Last season's runners up in the Russian Premier League, Rostov are the lowest ranked side left in the tournament but have enjoyed a best ever European campaign.
United finished second in Group A and reached this stage after an impressive 4-0 aggregate win over Ligue 1 outfit Saint-Etienne.
Having seen off Dutch giants Ajax in the play-offs, Rostov reached the Champions League group stage for the first time.
Drawn in the "Group of Death" alongside European heavyweights Atletico Madrid, Bayern Munich and PSV, their creditable third place finish sent them into the Europa League.
Under the tutelage of Austrian coach Ivan Daniliants, Rostov beat Carlo Ancelotti's side 3-2 in the home fixture and reached this stage with an impressive 5-1 aggregate win over Sparta Prague.
Last season's runners up in the Russian Premier League, Rostov are the lowest ranked side left in the tournament but have enjoyed a best ever European campaign.
United boss Jose described the tie as "bad in every aspect", and said:
"It's far to travel and it is difficult because the team is very defensive and physical, it is in a bad period for us.
"They had a very good Champions League campaign, they beat Ajax and Anderlecht in the qualifying and managed important results against Atletico and Bayern Munich, famous clubs, big clubs.
"They got third position to knock PSV out so it is a bad draw in every aspect but after Southampton and Bournemouth we focus on it and go for it."
Elsewhere, two of the tournament favourites will fail to progress beyond this round.
Lyon, who knocked out AZ Alkmaar 11-2, will face Roma and Schalke have been drawn with Monchengladbach in an all-German affair.
The full draw is: Celta Vigo v FC Krasnodar, APOEL v Anderlecht, Schalke 04 v Borussia Monchengladbach, Lyon v Roma, Rostov v United, Olympiakos v Besiktas, Gent v Genk, Ajax v Copenhagen
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