While the hosts recorded an impressive victory in LaLiga at Real Betis last time out, the German visitors continued their disappointing start to the season, with a 1-1 draw to Wolfsburg.
Match preview
With this season's surprise package, Club Brugge, already out of sight at the top of Group B, it is down to Porto, Atletico Madrid and Bayer Leverkusen to fight it out for the second qualifying spot for the Champions League knockout stages.
Following their 3-0 triumph in Leverkusen, the Portuguese side find themselves on six points, two ahead of Diego Simeone's men with four, and three ahead of Xabi Alonso's side, whose victory over Atletico in September has provided their only points of the campaign so far.
Only a win will do, therefore, for both sides at the Civitas Metropolitano on Wednesday, with just one more game remaining to catch Porto after this one, who travel to Bruges hoping to take advantage of the early qualification of the Belgian table-toppers.
Los Colchoneros struggled to break down Carl Hoefkens's side in Madrid two weeks ago, firing 21 shots at goal and accumulating 2.33 in expected goals as they fell to a deflating draw despite vociferous home support.
Their weekend win at the Benito Villamarin, however, should fill the Spanish side with confidence ahead of their European showdown, having beaten a Betis side who boasted a 100% record in front of their own fans before kickoff.
Antoine Griezmann was once again the difference, as the Frenchman continued his dazzling form with a goal directly from a corner, before squeezing home a second just 17 minutes later to seal a massive three points in Atletico's domestic campaign.
With their star striker on fire, and 68,000 Madrilenos behind them, Los Rojiblancos will be confident that they can get the job done.
Bayer Leverkusen, on the other hand, just cannot seem to build any sort of consistency at the moment, having lost 10 of their 18 games in all competitions so far this season.
Following a 5-1 thumping at the hands of Eintracht Frankfurt, Die Werkself missed a penalty, hit the woodwork, and scored a horror own-goal in a 2-2 draw to Wolfsburg on the weekend, in a game that just about epitomised the brilliant best and woeful worst of a talented side that somehow finds itself 15th in the Bundesliga.
It has not been easy for the German side in the Champions League either, as a 2-0 defeat in Portugal was followed up by a 3-0 loss to Porto in Western Germany, to see Leverkusen sink to the bottom of the group.
The long-term injury of Florian Wirtz has not helped Xabi Alonso's case as the new boss, but he will be hoping that a return to Spain can see a return to form for his young team, as they look to cause a mighty upset in the capital.
Atletico Madrid Champions League form:
W
L
L
D
Atletico Madrid form (all competitions):
L
W
D
W
D
W
Bayer Leverkusen Champions League form:
L
W
L
L
Bayer Leverkusen form (all competitions):
L
L
W
L
L
D
Team News
There do not seem to be any additional injury worries for Atletico Madrid after a busy few months in the treatment room, aside from Thomas Lemar, Koke and Marcos Llorente, who all continue to be sidelined with thigh problems.
Jan Oblak returned to the starting XI on Sunday against Real Betis after he suffered a head injury two weeks ago, and he will continue in goal in behind what should be a back four.
Up front, Alvaro Morata should join Griezmann up front, while Joao Felix will continue on the bench after a more positive cameo appearance on the weekend from the Portuguese youngster.
The visitors have also been unfortunate with injuries this campaign, as Wirtz edges closer to a return from his cruciate ligament rupture back in March.
Forwards Karim Bellarabi and Sardar Azmoun will miss out once again, while midfield enforcer Exequiel Palacios is ruled out with a hamstring injury.
The main man up front, Patrik Schick, missed the weekend's draw with Wolfsburg with adductor problems, but there is hope that the Czech international will be back for this one, with his absence on Saturday being played down as a precautionary move.
Atletico Madrid possible starting lineup:
Oblak; Reinildo, Savic, Gimenez, Molina; Carrasco, Kondogbia, Witsel, Correa; Morata, Griezmann
Bayer Leverkusen possible starting lineup:
Hradecky; Bakker, Hincapie, Tah, Tapsoba, Frimpong; Andrich, Demirbay; Diaby, Schick, Hudson-Odoi
We say: Atletico Madrid 3-1 Bayer Leverkusen
We are expecting an entertaining game here, as two talented sides battle it out in an all-or-nothing clash.
The visitors will be dangerous with the likes of Moussa Diaby on the break, but we think the quality of Simeone's side should be enough to seal a crucial win.