Reigning European champions Chelsea will face Sparta Prague in the last 32 of the Europa League .
The Blues, who failed to make the knockout stages of the top-tier European competition, will start their bid to become only the fourth club after Juventus, Ajax and Bayern Munich to win all of the major European trophies as they bid to usurp defending champions Atletico Madrid.
Tottenham will take on Ligue 1 side Lyon, starting with a home tie on February 14, while Liverpool face Russian champions Zenit St Petersburg and Newcastle take on Ukraine's Metalist Kharkiv.
Chelsea avoided a rematch with Atletico, who handed them a 4-1 drubbing in the Super Cup back in August, and as a seeded team will start their Europa League campaign in Prague.
Atletico drew Russian side Rubin Kazan as they bid to defend the title they won with a comprehensive 3-0 defeat of Athletic Bilbao in last year's all-Spanish final.
Liverpool travel to Zenit for their opening round of 32 match to face the Russian side who has hit the headlines this week when their largest supporters group, Landscrona, caused widespread outrage.
They posted an open letter on their website that outlined their preferred criteria for future signings at Zenit to exclude sexual minorities and non-Europeans from the playing staff.
Tottenham will play what could be one of the most hotly contested ties of the round when they face Lyon, who are a tough opponent more used to Champions League football.
Andre Villas-Boas' side could line up a last-16 meeting with Inter Milan if they can beat Lyon over two legs, and if the Serie A side can win their tie against Romania's Cluj.
It would be a much-anticipated match an evoke memories of when Gareth Bale scored a hat-trick at the San Siro for Tottenham against Inter in a match that eventually saw the north London side lose 4-3 in October 2010.
Tottenham general secretary Darren Eales expects a tough clash with Ligue 1's Lyon over the two legs.
"It's a tough draw and this is the first time in nine years they've not been in the Champions League,'' Eales told Sky Sports News.
"There are a lot of tough teams in the draw. We can ask Hugo (Lloris, Tottenham's former Lyon goalkeeper) the way to go and I think he will be excited about the chance to go back to his old team and play there.
"If we do get Inter if we do get through, two years ago in the Champions League when Gareth Bale got that wonderful hat-trick - that's an exciting game but we have to think about Lyon first."
And Eales believes Villas-Boas has what it takes to lead Spurs to the European title after he engineered a win for former club Porto during a treble-winning first season in charge which saw his side also lift the Portuguese Cup and win the Primeira Liga.
"He's got the pedigree so hopefully he can do what he did with Porto two years ago and we can go al the way to (the final in) Amsterdam," he said.
"We want to be playing in European competition. We don't see why we can't have a successful Europa League campaign and do well in the league."
In the other games, Champions League dropouts BATE Borisov face Turkey's Fenerbahce while Spain's Levante take on Olympiacos and Dynamo Kyiv take on Ligue 1's Bordeaux in their knockout ties.
Dutch champions Ajax host Steaua Bucharest first in their round of 32 tie while Germany's Stuttgart host Genk and Bayer Leverkusen play Portugal's Benfica.
Borussia Monchengladbach face Lazio while Swiss champions Basle play Dnipro of the Ukraine, Russia's Anzhi play Hannover and Napoli take on Viktoria Plzen.
Newcastle boss Alan Pardew admitted the club's Europa League adventure in Ukraine will be a trip into the dark.
The Magpies, who were paired with Metalist Kharkiv, face a lengthy journey as well as a tough tie when the competition resumes in February.
Asked what he knew about their next opponents, Pardew said: "Not much, really.
"I do know it's a long journey, I've had a look at that, and they won their group, so it's a tough agenda for us.
"It's a tough draw in terms of travel; the opposition, I know very little about. I can't even comment on that until such time as we do some studying."
UEFA Europa League Round of 32:
BATE vs Fenerbahce
Inter Milan vs CFR Cluj-Napoca
Levante vs Olympiacos
Zenit St Petersburg vs Liverpool
Dynamo Kiev vs Bordeaux
Bayer Leverkusen vs Benfica
Newcastle vs FC Metalist Kharkiv
VfB Stuttgart vs Genk
Atletico Madrid vs Rubin Kazan
Ajax vs Steaua Bucuresti
Basle vs Dnipro
Anzhi Makhachkala vs Hannover 96
Sparta Prague vs Chelsea
Borussia M'gladbach vs Lazio
Tottenham vs Lyon
Napoli vs Plzen
First legs to be played 14th February, 2013
Second legs to be played 21st February, 2013
UEFA Europa League Round of 16
Napoli/Plzen vs BATE/Fenerbahce
Bayer Leverkusen/Benfica vs Dynamo Kiev/Bordeaux
Anzhi Mackhachkala/Hannover 96 vs Newcastle/FC Metalist Kharkiv
VfB Stuttgart/Genk vs Borussia M'gladbach/Lazio
Tottenham/Lyon vs Inter Milan/CFR Cluj-Napoca
Levante/Olympiacos vs Atletico Madrid/Rubin Kazan
Basle/Dnipro vs Zenit St Petersburg/Liverpool
Ajax/Steaua Bucuresti vs Sparta Prague/Chelsea
First legs to be played 7th March, 2013
Second legs to be played 14th March, 2013