Manchester United will face Ligue 1 side Saint-Etienne in the Europa League round of 32, while Tottenham have been drawn to play Belgian team K.A.A Gent.
United's tie will pit midfielder Paul Pogba against his older brother Florentin, who is a defender for the French side.
Saint-Etienne won three and drew three of their qualifying encounters, and Christophe Galtier's team beat Anderlecht in their final Group C game to pip the Belgian outfit to top spot.
European Cup runners-up back in 1976, they are currently eighth in the Ligue 1 standings.
Boss Jose Mourinho welcomed the news that United face just a short trip to France, having taken his side to Turkey and Ukraine during their Group A campaign.
"The good thing is the travel," he said. "We were very unlucky in the group stage, now we go to France."
Regarding the clash of the Pogba brothers, he added: "Paul will be laughing, and for sure his brother will also be laughing.
"I think it's nice, it's happened in the history of football a few times."
Spurs qualified for the Europa League after finishing third in their Champions League group and will now tackle a K.A.A Gent side who finished second in Group H.
Gent were Belgian champions in 2014-15 and are currently fifth in the standings, albeit just three points behind the leaders.
Spurs will be meeting Gent in a competitive fixture for the first time and will be away for the second leg.
There were tough draws for the Italian sides, Roma having been paired with Villarreal while Fiorentina will take on Borussia Moenchengladbach.
The draw for the UEFA Europa League round of 32:
Athletic Bilbao v Apoel Nicosia
Legia Warsaw v Ajax
Anderlecht v Zenit St Petersburg
FC Astra Giurgiu v Genk
Man Utd v Saint Etienne
Villarreal v Roma
Ludogorets v FC Copenhagen
Celta Vigo v Shakhtar Donetsk
Olympiacos v Osmanlispor
AA Gent v Tottenham
Rostov v Sparta Prague
Krasnodar v Fenerbahce
Borussia M'gladbach v Fiorentina
AZ v Lyon
Hapoel Beer Sheva v Besiktas
PAOK Salonika v Schalke 04
Ties to be played 16th and 23rd February.