Diego Simeone's side hold a slender advantage heading into the Anfield encounter after Saul Niguez's early goal at Estadio Metropolitano last month.
Here are a trio of duels that could prove pivotal this evening...
Fabinho v Joao Felix
If selected to operate as a second striker, Felix's positioning may come into the area of the pitch Fabinho usually patrols.
Felix was unable to take part in the first leg due to injury, but he's hit the ground running since his return to action.
In Atletico's last three matches, the 20-year-old star has been on the scoresheet twice. He scored as a substitute in a win over Villarreal before netting as a starter in Saturday's 2-2 draw with Sevilla.
They represented his first goals for Atleti since December, with the Portuguese international having an interrupted campaign following his summer move from Benfica.
"He started with great enthusiasm," Simeone recently said. "He had two injuries that took him out of that continuity.
"He is looking for that continuity in the team again, that continuity we all need and expect from him.
"Hopefully he gets to where he suggested he could, because in the case of young boys it is a consequence of where one wants to go. If he wants to go far, he can."
Fabinho, too, is not long back after injury and will need to be at his best in order to nullify the threat of Felix.
Mohamed Salah v Jan Oblak
Liverpool need to be ruthless in the final third on Wednesday night and Salah, statistically speaking, is the likeliest source for the goals needed.
The Egyptian is the Reds' top goalscorer in all competitions this term with 20 – four of which have come in Europe.
But he'll have to beat one of the best backlines in the Champions League this season. Indeed, Atletico have conceded just five times in the 2019-20 competition so far, averaging out at 0.71 goals against per game.
And the very last line of their defence is Oblak, whose biggest admirer happens to be his manager.
"He is the best goalkeeper in the world," Simeone said last April. "We are fortunate that he chooses to play at Atletico and that he is with us."
Oblak had little to do in the first leg, not recording a single save throughout the 90. But when called upon, the Slovenian is widely renowned for his sublime shot-stopping qualities and ability to consistently pull off the spectacular.
It's up to Salah and co to find the part of the net where he can't get to.
Andy Robertson v Kieran Trippier
Jürgen Klopp will have Robertson available for this encounter after he sat out last weekend's victory over Bournemouth.
The left-back's willing runs up and down the channel mean he is almost certain to come up against Trippier.
With Liverpool needing to be on the front foot, Robertson and full-back partner Trent Alexander-Arnold can attempt to pin Atletico back with relentless pressure from out wide.
Robertson's only goal at Anfield this season came in the Champions League when he combined with Alexander-Arnold during a win over Salzburg.
The best angles of Robbo's run and finish against Salzburg
Meanwhile, Trippier was unavailable for the first leg due to a groin injury, but has appeared in every game since recovering from the issue.
The England international has enjoyed a hugely encouraging start to life in Spain after making the switch from Tottenham Hotspur in July.
Atletico will be hoping Trippier's experiences of combating Liverpool's left flank in the past can come in handy.