Zenit, UEFA Cup winners in 2008, have won only twice in 14 games against Spanish opponents and are without a victory in their last seven against La Liga opponents.
Fiorentina's reward for demolishing Serie A rivals AS Roma in the last 16 was a quarter-final against Dynamo Kiev, while Napoli play VfL Wolfsburg and Dnipro Dnipropetrovsk play Club Bruges, the only unbeaten side left in the competition.
The ties will take place on April 16 and 23 with Sevilla, Club Bruges, Kiev and Wolfsburg set to play the home legs first.
Sevilla, three-times winners of the competition, have eased into the last eight and made light work of La Liga rivals Villarreal in the last round, winning 5-2 over two legs.
"Zenit are one of the strongest sides in the draw," said Sevilla technical secretary Oscar Arias whose side beat Zenit in the last eight en route to their 2006 UEFA Cup title.
"It will be a very open but difficult game. We know we have to travel a long way, and that's a handicap, but that's the way the draw has worked out and it cannot be an excuse."
VfL Wolfsburg will fancy their chances against Italy's Napoli having dispatched Serie A Inter Milan comprehensively in the last round, 5-2 on aggregate.
Napoli, however, may prove cannier opposition under European specialist Rafa Benitez, who is seeking to become only the second man after Giovanni Trapattoni to win the trophy for a third time after victories with Valencia in 2004 and Chelsea in 2013.
(Reporting by Toby Davis; editing by Ed Osmond)
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