Sevilla, bidding for a record fourth title in the second-tier European competition, won last season by beating Benfica on penalties in the final in Turin.
But in their path this time are Standard Liege of Belgium and Dutch two-time UEFA Cup winners Feyenoord, in a Group G which also includes Croatian minnows Rijeka.
Sevilla coach Unai Emery descibed the draw as "good, nice and hard."
"There was very good teams, top teams," he continued. "Who says we are favourites? We're challengers. Any of the four can get to the next phase," added Emery.
English side Everton have been drawn in Group H alongside Wolfsburg of Germany, French side Lille and Turkish outfit Krasnodar, who advanced past Real Sociedad in the play-off round.
Eliminated by Porto in the Champions League play-offs, Lille can count on their tight defence which helped them to third in Ligue 1 last season.
Lille coach Rene Girard was anticipating a tough group.
"It is an extremely complicated draw. It is tough as Monaco's Champions League group (featuring Bayer Leverkusen, Zenit St Petersburg, Benfica). That gives you an idea of the size of the task," he said. "Playing in Germany or England for example will be great challenges."
In Group C, English side Tottenham Hotspur are favourites but face three tough trips to Besiktas in Turkey, Serbian side Partizan Belgrade and Greek outfit Asteras Tripolis.
Scottish champions Celtic avoided meeting Legia Warsaw, the side who they controversially beat in Champions League qualifying due to a technicality, and are in Group D alongside Salzburg, Dinamo Zagreb and Astra Giurgiu of Romania, conquerors of Lyon in the play-offs.
Celtic manager Ronny Deila told UEFA.com: "It's an interesting group. There are good teams but we are going to fight to go through. We are disappointed we didn't make the Champions League but we have to close this chapter for this year and remember the feeling we had.
"We have to work really hard, learn from our defeats and use that experience when we hopefully get in that situation again next year."
The four Italian clubs all drew groups which they are capable of advancing through, even if Inter Milan must be wary of Dnipropetrovsk and Saint-Etienne in their Group F which also includes first-timers Qarabag of Azerbaijan.
"Inter isn't the only difficulty in this group," Saint-Etienne sporting coordinator Dominique Rocheteau said. "Going to play in Ukraine is never easy."
Napoli should have an easier time against Sparta Prague, Swiss side Young Boys and Slovan Bratislava in Group I, as should Fiorentina, who are up against Greek side PAOK in Group K, which also includes Guingamp of France and Belarussian side Dynamo Minsk. Torino play Copenhagen, Club Brugge and Helsinki in Group B.
The six matches will take place on September 18, October 2 and 23, November 6 and 27 and December 11.
The top two from each group will qualify for the last 32 where they will be joined by the third-placed finisher from the Champions League group stages.
The final takes place in Warsaw on May 27 with this season's winners qualifying for next year's Champions League for the first time.
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