The Ligue 1 leaders went ahead through Idrissa Gueye after six minutes when Andreas Isaksson failed to deal with a corner, then Tulio De Melo doubled the lead just after the half-hour mark.
Having offered little for most of the game, PSV then struck back with two goals seemingly from nowhere - Wilfred Bouma netting in the 84th minute and Ola Toivonen completing the comeback 64 seconds later.
From having looked out of the match, it left PSV with the upper hand going into the second leg of their last-32 tie.
The writing looked to be on the wall for the Eredivisie leaders as early as the sixth minute when Lille took the lead.
Isaksson came for Ludovic Obraniak's corner but could only parry, and Gueye finished from the edge of the box.
Pierre-Alain Frau and Emerson both went wide as Lille pressed for a second, with their visitors struggling to establish themselves in the game.
The second duly arrived in the 31st minute in simple fashion as De Melo nodded home Mathieu Debuchy's right-wing cross from close range.
PSV finally fashioned a chance four minutes before the break and arguably Marcus Berg should have taken it, but his close-range effort was turned behind by Mickael Landreau.
The French dominance continued after the restart, as first Aurelien Chedjou and then Stephane Dumont sent strikes from distance wide.
Frau was next to try his luck, again missing the target, before Berg had another go at the other end.
He at least worked Landreau, though it was a comfortable save.
Chances became few and far between as the final whistle drew nearer, though Isaksson was called into action to turn a long-range free-kick from Yohan Cabaye behind after Francisco Rodriguez had fouled De Melo.
But from nowhere, with the game seemingly drifting to its conclusion, PSV launched a comeback.
First Bouma reacted to convert from close range after Toivonen's shot from the edge of the box hit the bar.
Then the Swede got on the scoresheet himself with a low finish from 18 yards to leave the home fans stunned.
Lille 2-2 PSV: Match Report - view commentary, squad, and statictics of the game as it happened.