Less than nine months on from lifting the trophy for a sixth time at the Estadio Wanda Metropolitano, Jurgen Klopp's side were beaten at the same stadium last month to leave themselves with a must-win second leg in front of their own fans.
Anfield needs no extra hype when it comes to European nights, and it promises to be a cauldron on Wednesday when Atletico, whose gamesmanship in the first leg irked the Liverpool fans and players alike, come to town.
The Spanish outfit have been masters of quietening crowds and stifling opposition over the years, and they did exactly that to Liverpool in the first leg when a vintage Diego Simeone display saw them prevent the Reds from having a single shot on target after Saul Niguez had given them a fourth-minute lead to protect.
Not many teams are more adept at holding on to a lead than Atletico and that is exactly what they will be expected to try to do on Wednesday night too. However, they will also know that keeping Liverpool at bay for 90 minutes at Anfield is arguably the toughest challenge in world football right now, while the lure of a priceless away goal could be enough to tempt them away from battening down the hatches completely, at least initially.
For Liverpool, the challenge will be to break down one of the most stubborn defences around. On paper that task looks simpler than their last home Champions League knockout game - the unforgettable 4-0 semi-final comeback win over Barcelona last season - but in its way it could prove to be even tougher.
It could take another moment of ingenuity - like Trent Alexander-Arnold's quick corner for Divock Origi to sweep home - to unlock a defence which would have been drilled with instructions about what to expect from the Liverpool attack.
It is a Liverpool attack which has not been firing on all cylinders lately, failing to score in three of their last five games, all of which ended in defeat after the Atletico loss sparked a dramatic slump in their previously relentless form.
Some of those results and performances can perhaps be put down to complacency with the Premier League title all-but sewn up, but that will certainly not be the case on Wednesday night in what promises to be such a highly-charged game.
The Reds could even be crowned English champions before they next play in the Premier League should Manchester City lose their next two games, although despite moving to within six points of the title at the weekend their focus will be firmly on Atletico now.
Saturday's win over Bournemouth came in timely fashion following back-to-back defeats, although it was by no means straightforward as Klopp's side were forced to come from behind once again and then failed to kill the game off in the second half, requiring a goalline clearance from James Milner to return to winning ways.
Had the Reds suffered another setback in that match then their confidence would have been further damaged ahead of Atletico's visit, but the win, coupled with Man City's derby defeat to Manchester United a day later, will have given them a much-needed boost in addition to keeping their imperious Anfield record alive.
Klopp's side have now won an English-record 22 successive league games in front of their own fans and are 55 without defeat, while in European competition they are unbeaten in their last 25 Anfield outings stretching back to October 2014.
Having now failed to keep a clean sheet in their last five games across all competitions, Liverpool will be encouraged by the fact that they have prevented the opposition from scoring in five of their last six home Champions League knockout games, including all three last season.
Indeed, there are plenty of reasons for optimism from a Liverpool perspective; they are unbeaten in two-legged European knockout ties under Jurgen Klopp, winning each of their last 11 in the Europa League and Champions League in a run which stretches back to 2014-15.
Liverpool have made it to the final every year they have had European competition with Klopp at the helm and it is now 11 years since they suffered defeat in a Champions League knockout tie - against Chelsea in 2008-09.
The Reds have also only ever lost one of their previous seven Champions League last-16 ties, although that did come when they were last holders of the trophy, at the hands of Benfica in 2005-06.
Liverpool have even managed to progress from nine of the 12 ties in which they lost the first leg 1-0 away from home - most recently against Spanish opposition in the shape of Villarreal four seasons ago - so this is a position from which they recover more often than not.
Atletico can boast plenty of impressive European statistics themselves, though, and have been one of the most consistent continental performers over the past decade, reaching two Champions League finals and three Europa League finals in that time.
With Simeone at the helm La Rojiblancos have won 25 of the 26 two-legged European ties in which they have prevailed in the first leg, although the exception to that came just last season when Juventus mounted a second leg comeback inspired by Cristiano Ronaldo.
That defeat to Juve means that Atletico have now won just one of their last nine away games in Champions League knockout ties, losing six, while they have also lost four of their last six away games in the competition including the group stages, their only win in that time coming at Lokomotiv Moscow.
Indeed, they could lose three successive away Champions League games for the first time with defeat to Anfield, and it is that away form which will be perhaps their biggest concern given Liverpool's strength in front of their own fans.
Atletico are yet to win a game on the road this calendar year, including a defeat to third-tier Cultural Leonesa in the cup, and remarkably have only won one of their last 13 away games across all competitions.
The majority of those have been draws, which of course would be enough for them to progress on Wednesday night, but it is in stark contrast to their home form, where they have lost just one of their last 26 outings.
The Champions League is Atleti's last hope of silverware this season and Simeone's side face a battle to even qualify for the competition again next season, currently sitting fifth in the table and a point outside the top four following Saturday's 2-2 draw with third-placed Sevilla.
All of the goals came in the first half during that tie and Liverpool will no doubt be buoyed to see Simeone's side concede twice, making it only one clean sheet in their last five outings.
Indeed, Wednesday's visitors have conceded more goals than they have scored on the road in La Liga this season, so it will take a huge rearguard action for them to hold on to their advantage on Merseyside.
Liverpool Champions League form: WWWDWL
Liverpool form (all competitions): WLWLLW
Atletico Madrid Champions League form: WWLLWW
Atletico Madrid form (all competitions): WDWWDD
Liverpool could be boosted by the return of captain Jordan Henderson, who has missed the last four games since limping off in the first leg with a hamstring injury but is now back in training.
Klopp is also hopeful of having Andrew Robertson back available after the defender missed the weekend win over Bournemouth with a slight injury.
Sadio Mane and Mohamed Salah were both on the scoresheet against Bournemouth, the latter of whom became the first Liverpool player to score at least 20 goals in three successive seasons since Michael Owen from 2000 to 2003.
Liverpool's attackers will certainly be hoping for more joy than they experienced in the first leg, although even if they get past the Atletico defence they will then need to beat Jan Oblak, who is due to make his 50th Champions League appearance and has kept 26 clean sheets in his previous 49 - a joint-competition high in that period.
Kieran Trippier, who played the full 90 minutes in last season's final as Liverpool beat his Tottenham Hotspur side, is a slight doubt after being seen limping following the weekend draw with Sevilla.
The fit-again Joao Felix, who missed the first leg, was also taken off with 10 minutes remaining on what was his first start since January - a decision which was jeered by the Atletico fans.
Liverpool have three players - Joe Gomez, Mane and Robertson - who will be banned for the next match should they pick up a booking, while Atletico's Angel Correa is also one yellow card away from suspension.
Liverpool possible starting lineup:
Adrian; Alexander-Arnold, Gomez, Van Dijk, Robertson; Henderson, Fabinho, Wijnaldum; Salah, Firmino, Mane
Atletico Madrid possible starting lineup:
Oblak; Trippier, Savic, Felipe, Renan Lodi; Saul Niguez, Partey, Koke, Joao Felix; Correa, Morata
Head To Head
This will be the sixth meeting between these two sides, with Liverpool winning just one of the previous five - a 2-1 home victory after extra time in the 2009-10 Europa League semi-finals which was not enough to seal their place in the final due to Atletico's 1-0 first-leg lead.
Liverpool will be hoping that history does not repeat itself on Wednesday, although their only other home game against Atletico ended in a 1-1 draw in November 2008, which would also see them crash out this time around.
The Reds have won their last four two-legged Champions League knockout ties against Spanish opposition, though, and nine of 11 overall despite winning only two of their last 11 individual fixtures against teams from La Liga.
Liverpool have won four of their last six home games against Spanish visitors, although their overall such record is less convincing with only six wins and five defeats from 18 - the most recent of which being their Barcelona comeback.
Atletico, meanwhile, have won just twice in 13 away games against English clubs, losing four times, but they have drawn 1-1 on each of their last three visits to England and are unbeaten in the last four.
La Rojiblancos have won all six previous ties in which they hosted English opposition in the first leg, while Derby County and Bolton Wanderers are the only English teams to have triumphed over them in 10 such two-legged knockout ties.
We say: Liverpool 2-0 Atletico Madrid
This promises to be a fascinating contest; two European knockout specialists from recent times going head to head, with the defence-minded Atletico looking to keep Liverpool's attack at bay.
The most important thing for Liverpool will be to score the first goal, while they will need to improve defensively if they are to avoid conceding a costly away goal at any point. However, this is a team which has risen to the big occasion on numerous occasions under Klopp and, given their record at Anfield compared to Atletico's record on the road, we are backing Liverpool to progress.