The Serie A side are one of the big favourites in the tournament this year, having brought in big names such as Ronaldinho and Andriy Shevchenko over the summer.
In other big ties Sevilla, winners in 2006 and 2007, start against Austrian side Salzburg while English outfit Portsmouth have been drawn against Portugal's Vitoria Setubal.Another of the competition favourites, Valencia, also face a trip to Portugal when they take on Maritimo.
Standard Liege, knocked out of Champions League qualifying by Liverpool, return to Merseyside to face Everton, while the Toffees' Premier League rivals Manchester City, after scraping past FC Midtjylland on penalties on Thursday, have been rewarded with a tie against Omonia of Cyprus.
Irish side St Patricks face a tough trip to the German capital after being drawn against Hertha Berlin.
Italian side Sampdoria will play Kaunas of Lithuania, while their Serie A rivals Napoli face one of the toughest draws of the round when they take on Portuguese giants Benfica.
Spanish side Racing Santander have been rewarded for a good campaign in the Primera Liga last season with a tie against Finnish club Honka Espoo, while league rivals Deportivo La Coruna also travel north to face Brann Bergen.
English sides Aston Villa and Tottenham face trips to eastern Europe to face Bulgarian team Litex and Polish champions Wisla Krakow respectively, while Scottish outfit Motherwell travel to France to face Nancy.
Also heading to France are former England coach Steve McClaren's FC Twente who face Rennes, while Dutch runners-up Ajax take on Borac and 2002 UEFA Cup winners Feyenoord play Kalmar of Sweden.
There will also be a Scandinavian derby as Norwegians Rosenborg travel to Denmark to face Brondby.
Czech champions Slavia Prague face Vaslui of Romania. Hamburg also travel to Romania to take on Unirea Urziceni, while fellow German club Borussia Dortmund have a tougher looking test against Serie A side Udinese.
St Etienne face Hapoel Tel Aviv, while Greek side Olympiacos face Nordsjaelland.
Here is the complete draw:
AC Milan (Ita) v FC Zurich (Swi)
Politechnica Timisoara (Rom) v Partizan Belgrade (Ser)
Hertha Berlin (Ger) v St Patrick's (Irl)
Banik Ostrava (Cze) v Spartak Moscow (Rus)
Metalist Kharkiv (Ukr) v Besiktas (Tur)
Portsmouth (Eng) v Guimaraes (Por)
Kayserispor (Tur) v Paris St Germain (Fra)
Sevilla (Spa) v Salzburg (Aut)
Wolfsburg (Ger) v Rapid Bucharest (Rom)
Sampdoria (Ita) v Kaunas (Lit)
Maritimo (Por) v Valencia (Spa)
Dinamo Zagreb (Cro) v Sparta Prague (Cze)
Manchester City (Eng) v Omonia (Cyp)
Young Boys (Swi) v Club Brugge (Bel)
Nancy (Fra) v Motherwell (Sco)
Everton (Eng) v Standard Liege (Bel)
Napoli (Ita) v Benfica (Por)
Bellinzona (Swi) v Galatasaray (Tur)
NEC Nijmegen (Ned) v Dinamo Bucharest (Rom)
Racing Santander (Spa) v Honka Espoo (Fin)
Apoel (Cyp) v Schalke (Ger)
Litex Lovech (Bul) v Aston Villa (Eng)
Austria Vienna (Aut) v Lech Poznan (Pol)
Vitoria Setubal (Por) v Heerenveen (Ned)
Brann Bergen (Nor) v Deportivo La Coruna (Spa)
Slavia Prague (Cze) v Vaslui (Rom)
Slaven Koprivnica (Cro) v CSKA Moscow (Rus)
Brondby (Den) v Rosenborg (Nor)
Chernomorets (Bul) v Stuttgart (Ger)
Rennes (Fra) v FC Twente (Ned)
Ajax (Ned) v Borac (Ser)
Tottenham (Eng) v Wisla Krakow (Pol)
FC Copenhagen (Den) v FC Moscow (Rus)
MSK Zilina (Svk) v Levski Sofia (Bul)
Borussia Dortmund (Ger) v Udinese (Ita)
Braga (Por) v Artmedia Bratislava (Svk)
Feyenoord (Ned) v Kalmar (Swe)
Hamburg (Ger) v Unirea Urziceni (Rom)
Hapoel Tel Aviv (Isr) v St Etienne (Fra)
Nordsjaelland (Den) v Olympiacos (Gre)
Ties to be played over two legs, scheduled for September 18 and October 2.