With chief tormentors Real Madrid and Cristiano Ronaldo both out of the competition, coupled with a favourable draw and some fine form post-lockdown, it looked like this might be the Rojiblancos' best chance to finally claim a European Cup.
But once again, it has ended in disappointment. And as in previous years, there is the feeling that Diego Simeone's side could have done more when it mattered most.
Simeone is a master in knockout ties, but perhaps he overthought this one. The Argentine approached the one-off match against RB Leipzig as if it were two and left Joao Felix on the bench for the second half.
Thomas Partey and Alvaro Morata were also left out of an Atleti XI which lacked some star quality. If seemed that the plan was to soak up the pressure and then take the initiative late on - but why wait?
It could have worked. Atletico were second best in the first half, but went in level at the break and even when Dani Olmo headed RB Leipzig in front, Felix came on to level from the spot after winning a penalty himself.
That should have been the moment for Simeone's side to take a step forward. Instead, as so often in the past, they took a step back. And ultimately, they paid the price.
Yes, there was an element of fortune about Tyler Adams' deflected winner. But Leipzig had been the more positive team for the entire match and Julian Nagelsmann's men received their reward.
Atletico, of course, have been here before. The Rojiblancos had their hearts broken in Lisbon, scene of this match, by Real Madrid in the 2014 final and again two years later as they sat back in extra time and then lost on penalties.
Simeone's side had been dead on their feet in that first final, but were fresher in Milan and still opted to defend. In the shootout, they won the toss and went second. Real Madrid could not believe their luck.
Last season, the final at their Wanda Metropolitano home presented another opportunity. But after a fine 2-0 win at home to Juventus, it was thrown away on an awful night in Turin.
Many of the fans blamed Antoine Griezmann for that loss after it emerged that the French forward had been in talks with Barcelona ahead of the second leg.
But against Leipzig, they were outfought and beaten to so many second balls. Some of the things they used to do so well are not working right now.
Has the squad been built correctly for Simeone's style of play? Probably not. And Diego Costa, his trusty soldier from bygone battles, no longer looks up for the fight.
Credit to RB Leipzig, who were deserved winners, but this tie was there for the taking and the Rojiblancos retreated when they needed to attack. It is becoming a habit.
In his pre-match press conference, Simeone praised Leipzig's "fantastic coach" and Nagelsmann deserves even more praise after this win.
Simeone less so on this occasion. The Argentine has changed the history of Atletico Madrid and came so close to winning the biggest prize of all – the only one to have eluded both him and his club.
Victory over Jurgen Klopp and Liverpool in the last 16 showed he still has the tactical nous and the motivational qualities to lift his team for huge highs, but even those wins involved a fair amount of luck.
Nagelsmann is one example of how coaches are evolving, even at smaller sides, and the feeling is that Simeone will need something similar if he is ever to achieve his holy grail of Champions League glory at Atletico.