Atleti knocked out holders Liverpool in the last round and are in the quarter-finals for a fifth time in seven seasons, while Leipzig have made it to this stage for the first time.
It has been exactly five months since Atletico dumped a much-fancied Liverpool side out of the competition, helped by a calamitous display from stand-in goalkeeper Adrian.
Diego Simeone's men have made a habit of upsetting the odds on the continent and, after a couple of defeats in the final over the past six years, this may just be their season.
The draw has been kind to Los Rojiblancos, putting them up against quarter-final debutants Leipzig first and then one of Atalanta BC or Paris Saint-Germain in the semi-finals.
Atletico will enter this one-legged tie in good shape, too, having gone 18 matches without defeat either side of the coronavirus-enforced shutdown.
Diego Simeone credited the victory over Liverpool for reigniting his side's campaign, claiming that it gave his players belief that they are good enough to beat any team.
After finishing third in La Liga behind the big two, Atleti's full focus is now on the biggest trophy in club football, and they have a good record against German opposition.
Los Rojiblancos have always progressed against Bundesliga sides in the knockout stages of the Champions League - versus Bayer Leverkusen in 2015 and Bayern Munich in 2016.
However, Leipzig will see this as a massive opportunity to create some history of their own by going all the way in the reformatted competition.
Julian Nagelsmann's charges also finished third in their domestic league, ending the season with just one defeat in their final 15 matches - that coming against Borussia Dortmund.
On the continent, Leipzig topped their group before easing to a 4-0 aggregate win over Tottenham Hotspur in the first knockout round.
Timo Werner opened the scoring from the penalty spot in that tie but, in what is a major blow to Leipzig's hopes of progressing, he has since joined Chelsea.
The Red Bulls still have a number of talented players in their ranks, of course, and how they cope without Werner could well determine which of these sides makes it through.
RB Leipzig Champions League form: WWDDWW
RB Leipzig form (all competitions): WDWDLW
Atletico Madrid Champions League form: WLLWWW
Atletico Madrid form (all competitions): DWDWWD
Both players will self-isolate at home and will therefore play no part on Thursday, though Vrsaljko has been used sparingly this term and was already injured.
All other tests came back negative, meaning that the game has been given the all clear by UEFA to go ahead as planned.
Those two absentees aside, Simeone has a fully fit squad to choose from, with his biggest call coming up top.
That will mean retaining the same 3-5-2 setup that has worked so well for the club, but his hand may be further forced as Poulsen missed the end of the domestic campaign with an injury.
The German side may also be a little rusty given that this is their first competitive match in more than five weeks.
RB Leipzig possible starting lineup:
Gulacsi; Klostermann, Upamecano, Halstenberg; Mukiele, Laimer, Sabitzer, Angelino; Nkunku, Olmo; Schick
Atletico Madrid possible starting lineup:
Oblak; Trippier, Savic, Gimenez, Lodi; Llorente, Partey, Saul, Koke; Felix, Costa
We say: RB Leipzig 0-0 Atletico Madrid (Atletico through on pens)
Leipzig have kept a clean sheet in three of their last five European matches, while Atleti showed against Liverpool in the first leg that they can strangle the life out of opponents. It all points towards a tight and nervy encounter in Lisbon, one that we can see going all the way to penalties.