The Portuguese side won the UEFA Cup in 2003 when they beat Celtic in the final in the same city under coach Jose Mourinho, who went one better the following year by leading them to the Champions League.
Porto have so far had an outstanding season, losing only once in 33 matches in all competitions.
They swept through the group stage of the Europa League, dropping only two points, and their Colombian striker Radamel Falcao Garcia is leading scorer in the competition with seven goals.
"There will be great emotions returning to Seville," said coach Andre Villas-Boas. "It's a city with great meaning to all Porto fans. It's a good trip and Sevilla are prestigious opponents."
Brazil striker Luis Fabiano will be especially keen to do well, having scored only three goals during his only season with Porto in 2004.
He has been with Sevilla ever since.
Sevilla are also smarting from a defeat by Porto's neighbours Braga which denied them Champions League football this season.
Uruguay striker Luis Suarez will have to sit out Liverpool's visit to Sparta Prague as he is ineligible following his move from Ajax Amsterdam but his compatriot Edinson Cavani is seen as the major threat as Napoli host Villarreal.
Cavani scored five goals in the group stage to help Napoli secure their place as Italy's only representatives in the knockout stage.
The competition will have a strong Eastern influence with four teams from Russia, two from Ukraine and one each from Poland, Czech Republic and Belarus among the 32 survivors.
Portugal also have four representatives with Benfica, Braga and Sporting lining up alongside Porto.
Two of the Russian teams visit Switzerland with Spartak Moscow at FC Basel in a meeting of two teams who parachuted in from the Champions League and Zenit St Petersburg visiting Young Boys Berne's artificial pitch.
