Liverpool and Fulham left with home-work to do
Hamburg SV and Standard Liege also won 3-1 while there were 1-1 draws between Rubin Kazan and VfL Wolfsburg, Valencia vs Werder Bremen and Benfica against Olympique Marseille plus a goalless affair in the Atletico Madrid vs Sporting tie.
The pressure on Liverpool manager Rafa Benitez continued after his side were undone by a fortuitous free-kick from teenage Belgium forward Hazard with just minutes left on a cold night.
The visitors, whose only chance of a trophy this season is in Europe's second-tier competition, started with an attacking lineup of Fernando Torres, Ryan Babel, Dirk Kuyt and Steven Gerrard while Lille were without their top striker Gervinho.
After shading the first half and having a close-range Torres header superbly saved by Mickael Landreau, Liverpool almost went behind after the break when Daniel Agger's attempted clearance narrowly missed his own goal.
Lille's winner came in equally bizarre fashion with six minutes remaining, when Hazard's long-range freekick evaded everyone including Liverpool goalkeeper Pepe Reina to hand the French side a slender advantage for the second leg.
However, Benitez remains confident of securing a quarter-final berth.
"Lille are a good side, with good players and they are dangerous. We will play a difficult game at Anfield but have confidence we can beat them," the Spaniard told reporters.
The competition's other big name, twice European champions Juventus, eased past underdogs Fulham with first half goals from Nicola Legrottaglie, Jonathan Zebina and David Trezeguet.
The hosts, who surprisingly started with 23-year-old forward Antonio Candreva in favour of stalwart Alessandro Del Piero, went ahead early through Legrottaglie's powerful header and a superb Zebina strike.
Fulham rallied and struck lucky soon after with a deflected Dickson Etuhu shot before Trezeguet grabbed a third with the final kick of the first half, knocking the ball home after his initial strike came back off the post.
Dutch striker Ruud van Nistelrooy marked his first start for Hamburg with a goal in a comfortable victory over Anderlecht.
Strikes from defender Joris Mathijsen and compatriot Van Nistelrooy put the hosts ahead but Anderlecht hit back with a long-range Jonathan Legear freekick just before the break.
The Belgian side, who started with 16-year-old Romelu Lukaku up front, went further behind with 15 minutes to go when Hamburg captain David Jarolim volleyed home.
Last season's beaten UEFA Cup finalists Werder Bremen drew in Valencia after captain Torsten Frings converted a first-half penalty to put them ahead. Juan Mata equalised just before the hour mark minutes after team mate Ever Banega was sent off.
Russian champions Rubin Kazan were also held at home by Wolfsburg after Zvjezdan Misimovic's sweet strike cancelled out midfielder Christian Noboa's first-half header.
Sporting managed a draw at Atletico despite finishing the match with nine players and would have grabbed an unlikely victory if striker Liedson's shot had not hit the bar.
The Portuguese side lost defender Leandro Grimi to a second yellow card after half an hour and Tonel was later shown a straight red with just minutes remaining.
Belgian side Standard Liege comfortably beat Panathinaikos courtesy of an early Alex Witsel header and strikes from highly-rated forward Milan Jovanovic and Igor De Camargo.
Loukas Vintra's second-half header was the only reply from the hosts who had Simao sent off late on.
Marseille will take a precious away goal back to France after Hatem Ben Arfa's 90th minute header cancelled out Maxi Pereira's bundled goal to earn a draw at Benfica.
The second legs will be played on March 18.