The Reds are closing in on their first league title for 30 years but will be determined to pick up a positive result at the Wanda Metropolitano ahead of the second leg at Anfield on March 11.
Having won just one of their last seven matches in all competitions, it would be fair to say that Atletico will not enter Tuesday's clash with the European champions in the best of form.
Atletico have been dumped out of the Copa del Rey and lost in the Spanish Super Cup final since the turn of the year, in addition to suffering league defeats to Eibar and Real Madrid.
Atletico also lost two of their six matches in the group stages of the Champions League but still managed to finish second in the section behind Juventus to advance to the last-16 stage of the competition.
Tuesday's clash will actually be just the fifth meeting between Atletico and Liverpool in European competition, and the Spanish giants triumphed on away goals following a 2-2 draw when they last locked horns in the semi-finals of the 2010 Europa League.
It will be the first time that these two teams have faced each other in the Champions League since the group stages of the 2008-09 competition, when both matches finished 1-1.
Atletico might be the underdogs heading into this two-legged fixture, but they have won four of their last six ties in the round of 16 and have lost just once in 12 visits from English clubs, winning seven times in the process during an impressive run of form.
Los Rojiblancos have also reached two Champions League and three Europa League finals in the last 10 seasons, which is an indication of their pedigree. As a result, Liverpool will certainly be wary of the threat that the capital giants could provide despite their struggles this term.
Diego Costa's absence through injury has hit them hard in the final third, though, and there will be a lot of pressure on Alvaro Morata, who returned from injury in the 2-2 draw with Valencia on Friday night, to score the goals against Jurgen Klopp's side.
The fact that Liverpool played on Saturday evening against Norwich City - recording a 1-0 victory - while Atletico were in action on Friday should hand the Spanish side an advantage in terms of recovery.
The Reds are so comfortable in England's top flight, though, and the clash with the Canaries, which was decided by a Sadio Mane effort, was not too taxing for the runaway league leaders.
Klopp's team are now 25 points clear of Manchester City at the top of the Premier League table, while their presence in the FA Cup means that the treble is very much on for the club this season.
In terms of this season's Champions League, Liverpool won Group E with 13 points, one clear of second-placed Napoli despite losing to the Italian side on Matchday One. Winning back-to-back European Cups would be some achievement for the club, but there is still a long way to go in the competition.
The Merseyside giants beat Bayern Munich, Porto and Barcelona to make the 2019 Champions League final, where they won a sixth European Cup courtesy of a 2-0 success over Tottenham Hotspur.
The Reds have actually won their last 11 two-legged European ties, while they have been victorious in nine of their last 12 European fixtures, suffering just one defeat in the process during an incredible run.
History suggests that Liverpool will progress from this two-legged tie considering that they have won six of their previous seven last-16 ties in this competition. That said, the Premier League leaders have lost seven of their last 13 UEFA matches outside of England.
It would be fair to say that Atletico are not the same team as previous seasons, but Liverpool are enjoying a quite remarkable campaign. The Reds have won their last four matches in all competitions without conceding, although Napoli's two performances against them earlier this season will hand Atletico some hope.
Simeone will just want to stay in the contest ahead of the second leg at Anfield next month, and it is shaping up to be a fascinating clash in the Spanish capital on Tuesday night.
Atletico Madrid Champions League form: DWWLLW
Atletico Madrid form (all competitions): LLDLWD
Liverpool Champions League form: LWWWDW
Liverpool form (all competitions): WDWWWW
Atletico will again be without the services of injured forwards Costa and Joao Felix, while former Spurs defender Kieran Trippier will also miss out on the chance to face Liverpool due to a groin issue.
Jose Gimenez was named on the bench against Valencia on Friday and could return from a muscular problem against the European champions, though, while Morata also featured against Los Che.
Santiago Arias also played in Atletico's last match having recovered from an adductor problem, and it seems likely that the full-back will be handed a spot in the XI for this contest.
As for Liverpool, Mane and James Milner are both fit having made their returns from injuries against Norwich on Saturday, and the former will be in the starting XI on Tuesday night.
Atletico Madrid possible starting lineup:
Oblak; Arias, Savic, Gimenez, Lodi; Vitolo, Koke, Thomas, Saul; Morata, Correa
Liverpool possible starting lineup:
Alisson; Alexander-Arnold, Gomez, Van Dijk, Robertson; Henderson, Fabinho, Wijnaldum; Salah, Firmino, Mane
Head To Head
As mentioned, Tuesday will be just the fifth meeting between these two teams in European competition.
Atletico progressed from their Europa League semi-final on away goals in 2010, while the two teams played out two 1-1 draws in the group stages of the 2008-09 Champions League.
We say: Atletico Madrid 1-1 Liverpool
Under the lights at the Wanda Metropolitano, Atletico are certainly capable of picking up a positive first-leg result. Liverpool have not exactly been blowing teams away in recent months, but there is no question that a score draw would also be seen as a favourable result for the reigning champions.