Away goals from Saul Niguez, Antoine Griezmann, Kevin Gameiro and Fernando Torres saw Atletico Madrid leave Germany with a 4-2 victory and with one foot in the Champions League quarter-finals, even if Karim Bellarabi's strike and Stefan Savic's own goal gave Bayer Leverkusen a slither of hope ahead of the return leg.
Roger Schmidt's side took Los Rojiblancos all the way to penalties when they met at this stage two years ago, but they'll need to score at least three times at the Estadio Vicente Calderon after the Spanish side scored four times in a Champions League game for just the second time.
The 2015/16 runners-up started brightly, almost taking the lead in the 12th minute with a double opportunity.
Firstly, Griezmann was slid through one-on-one by Saul, but Bernd Leno was able to parry, after which Filipe Luis whipped such a dangerous ball back into the box that a flustered Wendell whacked a swiped clearance off his own crossbar.
Diego Simeone was frustrated on the sidelines, but he wouldn't have to wait long for his first away goal of the evening.
Saul has a knack of scoring with that star-emblazoned ball and he did so once again, jinking inside Aleksandar Dragovic in the 17th minute before curling around Leno for his fifth Champions League goal.
Bayer were stunned and a defensive error quickly took their and Dragovic's night from bad to worse.
The Austrian bungled a clearance backwards, with Gameiro alert enough to pinch possession and to race towards the penalty area, where he nudged the ball to the incoming Griezmann for Los Rojiblancos' second.
Kevin Kampl tried spark the Bundesliga team into life with a couple of long-range efforts around the half hour mark, but Miguel Angel Moya - preferred to the just-recovered Jan Oblak - was able to stretch enough to prod the first out for a corner, while the Slovenian's second effort flew wide.
In the 34th minute, the ball was back up the other end on an Atleti counter attack and Gameiro almost set Griezmann up for another, but the No.7's shot was blocked this time by the home goalkeeper to keep the half-time deficit at two.
Within three minutes of the restart, they had pulled themselves within one, with Bellarabi turning in Benjamin Henrich's low cross from the right flank.
Los Colchoneros responded well, though, and almost restored the lead straight away when Gameiro struck the angle of the crossbar and the post.
They did indeed grab a third when Dragovic's night went from worse to terrible as he conceded a penalty when pulling back Gameiro - although the contact did start outside the area.
Atletico have struggled from the spot this season, but the centre-forward duly converted straight down the middle.
Undeterred, the home side kept going and benefitted from a slice of luck when Moya palmed a low cross straight into Savic, who could do nothing as the ball trickled into the net.
Filipe Luis had to make a goal-line clearance from Javier Hernandez as the home side pushed for a leveller, but substitute Torres was on hand to score a late header and stall the comeback.
Match Sheet:
2 - Bayer Leverkusen: Leno; Henrichs, Dragovic, Toprak, Wendell; Bellarabi (Pohjanpalo, 66), Aranguiz, Kampl, Brandt (Bailey, 87), Havertz (Volland, 56); Chicharito.
4 - Atletico Madrid: Moya; Vrsaljko, Savic, Gimenez, Filipe Luis; Saul, Gabi, Koke, Carrasco (Torres, 78); Gameiro (Thomas, 71), Griezmann (Correa, 78).
Goals: 0-1 (Saul, min 17), 0-2 (Griezmann, min 25), 1-2 (Bellarabi, min 48), 1-3 (Gameiro, min 68), 2-3 (Savic own goal, min 68), 2-4 (Torres, min 86)
Referee: Willie Collum
Yellow cards: Henrichs (min 15), Dragovic (min 58), Wendell (min 64), Aranguiz (min 74), Torres (min 88), Gabi (min 89), Filipe Luis (min 90)
Stadium: BayArena
