Jurgen Klopp's side were on cloud nine after going 2-0 up within just 15 minutes of the first leg, but the Reds were powerless to quell the subsequent Blancos onslaught in a painful 5-2 defeat.
Needing to score four unanswered goals to keep their European dream alive, Liverpool do not exactly have momentum on their side going into the second leg, having been put to the sword 1-0 by Bournemouth at the weekend.
Meanwhile, Carlo Ancelotti's reigning champions overcame Espanyol 3-1 in La Liga last time out, but there is also the small matter of El Clasico next Sunday to take into account for the hosts.
Here, Sports Mole takes a closer look at Real Madrid and Liverpool's head-to-head record ahead of Wednesday's clash at the Bernabeu.
The demolition job at Anfield marked the 10th meeting between Real Madrid and Liverpool in the top tier of European football, with Los Blancos now boasting six wins compared to Liverpool's three.
One draw has also been played out by the two teams with 20 European Cup titles between them, and Real Madrid can boast six wins from the last seven showdowns after losing each of their first three battles.
Alan Kennedy wrote his name into Liverpool folklore when scoring the only goal in the 1981 European Cup final against Real, whose misery against the Reds would not be snapped in the 2008-09 last 16.
Yossi Benayoun made the net ripple at the Bernabeu in the first leg, and there would be no remarkable turnaround at Anfield for Real Madrid in the second leg, where Steven Gerrard struck a brace alongside Andrea Dossena and Fernando Torres's efforts.
However, not since that 4-0 thumping just over 14 years ago have Liverpool experienced success against Real Madrid, who eased to a pair of 3-0 and 1-0 wins in the 2014-15 group stage when Brendan Rodgers was at the Anfield helm.
The curse would not be lifted in Kyiv three years later, as two helping hands from Loris Karius alongside a Gareth Bale goal for the ages propelled Real Madrid to a 3-1 victory in the 2018 final before the COVID-19 pandemic raged across the globe.
No fans were present to witness Real and Liverpool lock horns in the 2020-21 quarters, where Vinicius Junior (2) and Marco Asensio gave Los Blancos a 3-1 first-leg win at Estadio Alfredo Di Stefano before a goalless draw at Anfield sent Zinedine Zidane's crop through.
Vinicius was again on target when Real inflicted final heartbreak on Liverpool last season, but the chaos outside the Stade de France will forever overshadow that contest, and few could believe what they had laid witness to when Ancelotti's team stormed back to put five past the Reds at Anfield three weeks ago.
At the time, Klopp refused to rule out the possibility of his side pulling off a miraculous fightback - having overseen that infamous 4-0 win over Barcelona in 2019 after a 3-0 first-leg loss - but there will be no Divock Origi to prod home any quickly-taken corners this time around.