Remi Garde's side enter the competition courtesy of a third-place finish in France last season, holding off the likes of Nice and Saint-Etienne who ended fourth and fifth respectively.
Lyon reached the semi-finals of the competition in the 2009-10 season, but were beaten 4-0 by eventual runners-up - and 2012-13 winners - Bayern Munich.
Russian Premier League runners-up Zenit St Petersburg take on FC Nordsjaelland of Denmark.
Both sides reached the group stages of last year's competition, but were ultimately unsuccessful in their attempt to reach the first knockout phase.
Meanwhile, Fenerbahce will face off against Austrian Salzburg after their reprieve from the Court of Arbitration for Sport (CAS) on Thursday.
The Turkish team were originally suspended from European competition for two years by UEFA amid allegations of match-fixing, but the CAS has now ruled they can feature in the draw, with a decision on their future participation due on August 28.
Dutch side PSV Eindhoven take on Belgium's Zulte Waregem, while PAOK of Greece take on Ukrainian team Metalist.
Scottish champions Celtic are likely meet Elfsborg. Neil Lennon's side - who reached the first knockout round of last season's Champions League - beat Cliftonville 3-0 in their second qualiying round first leg this week, while Swedish outfit Elfsborg routed Daugava Daugavpils 7-1.
The winners from the third round of qualifying will enter a play-off phase to determine the sides who will compete in the group stages, which begin on September 17 and 18.
Draw in full:
Lyon v Grasshopper Zurich, Nordsjaelland v Zenit St Petersburg, PSV v Zulte Waregem, PAOK v Metalist, Salzburg v Fenerbahce, Basel v Maccabi Tel Aviv or Gyor, Dinamo Tbilisi or EB/Streymur v Steaua Bucharest, Apoel v Birkirkara or Maribor, Slovan Bratislava or Ludogorets v Shirak or Partizan, Sligo Rovers or Molde v The New Saints or Legia Warsaw, Celtic or Cliftonville v Elfsborg or Daugava Daugavpils, BATE Borisov or Shakhter Karagandy v Neftchi or Skenderbeu, Austria Vienna v Ekranas or Hafnarfjordur, HJK Helsinki or Kalju v Viktoria Plzen or Zeljeznicar, Fola Esch or Dinamo Zagreb v Sheriff or Sutjeska