Holders Barcelona will play Bayer Leverkusen, a team famous for fading in the final straight, while their arch-rivals Real Madrid face a trip to icy Moscow in the Champions League round of 16 following the draw on Friday.
Bayern Munich, whose Allianz Arena will host the final, take on FC Basel, the underdogs who spectacularly ousted Manchester United, in another of the top ties.
Seven-times champions AC Milan will face Arsenal in one of two Italian-English ties, with Napoli, in the knockout rounds for the first time after Manchester City were eliminated, facing Chelsea.
Arsenal have advanced on all eight occasions when they have met Italian teams in the knockout rounds.
Surprise packages APOEL Nicosia, the first Cypriot club to reach this stage, will play Olympique Lyon. The other matches pitch Zenit St Petersburg against Benfica, who were last European champions 50 seasons ago, and 1993 champions Olympique Marseille against three-times winners Inter Milan.
Barcelona were happy to draw a side currently sixth in the Bundesliga, especially as it spared them a journey to Moscow.
"We got Bayer, well, perfect. All the teams have their positives and negatives. Like all things in life, you can focus on the rough and the smooth," said Barcelona president Sandro Rosell.
"With the Russian teams, for example, we preferred not to get one of them due to the plane trip, the fact you have to travel a day earlier and the cold, but, on the other hand they are in pre-season."
Barca's sporting director Andoni Zubizarreta told reporters: "German teams are always tough. I have always liked German football. They have stadiums that are full of passion, emotion and young people and it seems to me an excellent place to go and play."
Leverkusen, who earned the nickname Neverkusen after finishing second in the Champions League and Bundesliga in the 2001-02 season, were delighted.
"We are playing against the defending champions and are of course the clear outsiders," said sporting director Rudi Voeller.
"Both for our fans and young players, this is a dream draw... Everyone must play their best and Barcelona could have a bad day."
Leverkusen, where former Germany captain Michael Ballack is playing out his career, have finished second in the Bundesliga five times, including last season, but have never won it.
Real's former striker Emilio Butragueno, who still remembers playing in minus seven degrees Celsius in Russia during his career, was shivering at the mere thought of the trip to Moscow.
"We have to be careful, the temperatures will be low in Moscow on those dates, we are not used to that, it could be a problem," he told Reuters.
"It's an element that can have an impact on that game. The artificial pitch will also be a novelty."
UEFA guidelines recommend that matches be postponed if the temperature is below minus 15 Celsius.
However, in last season's Europa League, Dutch club Twente Enschede complained that UEFA officials had wrongly registered the Moscow temperature as minus 14 Celsius when other readings were one or two degrees lower.
Bayern beat FC Basel home and away in last year's group stage but were not taking the Swiss side lightly.
"If we remain focused and play with full force then we have a good chance to move into the quarter-finals," said Bayern CEO Karl-Heinz Rummenigge on the club website (www.fcbayern.de). "But please, no underestimating Basel."
"To be among the sixteen is exceptional; we should be aware of where we are and where we went to go," said FC Basel director Bernhard Heusler.
Arsenal will be attempting to repeat their 2007/08 performance when they won at San Siro on their way to knocking out AC Milan.
"Arsenal has always been fantastic for developing young talents," said Milan director Umberto Gandini.
"They have an outstanding player in (Robin) Van Persie. I know they have a few injuries, they have changed many faces but they are always strong and they have a fantastic coach in Arsene Wenger."
Arsenal director David Miles said: "There are other teams we would have preferred. It's the tie of the round, two fantastic games of football, our recent history against AC Milan is good."
Napoli's home record could be a worry for Chelsea as they have not been beaten in their San Paolo stadium in European competition for 17 years.
"It will be difficult, we've already seen from their group performances," Chelsea secretary David Barnard said.
"It will be a good occasion, a new experience for us. The feeling is upbeat, it's always been there and I think just because a few results haven't gone our way people have assumed people are not together."
The first legs will be played on February 14/15 and 21/22, with the return legs on March 6/7 and 13/14.