The hosts started fast in the match and were almost a goal up inside three minutes, only for Roberto Soldado to squander a double chance. However, he made amends 60 seconds later when he played in Cédric Bakambu who did what his striker partner couldn't and finished the opportunity.
Leverkusen struggled to create against a sturdy back line, and when they did they failed to take their chances as Javier Hernandez headed a rare one right at his opposing goalkeeper.
The Yellow Submarine were instead very potent on the attack, and they doubled their advantage just short of the hour when Bakambu exploited the visitors on the counter with his lightning pace and a devastating finish to match.
Villarreal could have added to their lead, but they could happily settle for just the two goals in the end, whilst Leverkusen's day got worse in stoppage time when Tim Jedvaj was sent off for a second yellow, meaning he is suspended for the return leg.
Early advantage for the Yellow Submarine
This was always going to be an intriguing tie, with both teams deploying the traditional but now unfashionable - at the top level, at least - formation of 4-4-2.
With both opting for two strikers, plenty of chances were expected too, and when the first came within three minutes of kick-off, this expectation was justified.
It was Villarreal who came close to breaking the deadlock; Mario Gaspar bombing forward and drilling the ball into the box, but Soldado's initial effort was saved by Bernd Leno, whilst his follow-up was blasted wide of the mark.
However, he would not rue these misses for long as, just a minute later, he teed up Bakambu to open the scoring. It was a lovely delicate hooked ball through for his strike partner, and the DR Congo international finished coolly to give his team a very early upper hand.
Hosts good for their lead - and they double it
Leverkusen could have levelled at the midway point of the first period, only for Hernandez's header to lack clinical direction. The Mexican's movement and leap was good, but he could only nodd Jedvaj's cross right at Alphonse Areola in the home goal.
Nonetheless, bar this chance, they struggled to threaten a Villarreal side with a terrific defensive record and the Spaniards came within inches of a second goal as we neared the break, only for Leno to pull off a top save.
Soldado has rediscovered the prolific form that evaded him at Tottenham Hotspur since joining the Yellow Submarine, and his movement to meet Samuel Castillejo's cross to near post showed this. The flick he produced upon contact exuded confidence too, but Leno's reflex save denied the Spaniard a sublime goal.
The interval didn't disrupt Villarreal's rhythm either, with Bakambu firing wide from a tight angle inside the opening five minutes of the second half.
The striker was clearly in the mood for goals though and he would bag his brace before the hour, racing away from Leverkusen's sleeping back line to latch onto Denis Suárez's through ball and power it through the legs of Leno, completing a perfect counter-attacking move.
The Germans were applying the pressure as they searched for a crucial away goal, but they were punished for their lack of focus at the back with devastating effect.
Leverkusen's late push in vain
Two goals down and in need of something good to take into their home leg, Leverkusen pushed on in search of a potentially crucial away goal.
However, with just 19 goals conceded in their 28 La Liga games this season, the Villarreal defence wasn't going to crack under just any pressure, with a real moment of quality to be the only thing able to puncture their chances of another clean sheet.
Leverkusen couldn't produce this though and, instead, the Spanish side came within fingertips of adding a third as substitute Leo Baptistão headed Nahuel Leiva's cross goalwards, only for Leno to push it over his bar to keep his team in the tie.
As they aim to scrap their way back into contention for qualification in the second leg, the Werkself will be without right-back Jedvaj too after he was sent off in stoppage time to compound Leverkusen's misery - shown a second yellow card for handball.
His dismissal concluded a dismal day out for the Germans and their faithful fans, who have it all to do in a week's time.