The two clubs have lifted the famous trophy 10 times between them, but this will be the first time that they have gone head to head for 54 years.
You have to go back to 1966-67 - before either of these clubs had been crowned European champions - for the last meeting between the two sides.
On that occasion Ajax ran out 7-3 winners on aggregate to reach the quarter-final, with Johan Cruyff - after whom the stadium where the two clubs will meet again is now named - scoring three of Ajax's goals.
If the goal-laden start to the Premier League season is anything to go by, and given that Liverpool have already been involved in two 7-2 scorelines this term, Wednesday's match alone may not be too far off that 10-goal tally.
Liverpool go into the game looking to put a painful Merseyside derby experience behind them in every sense as they were denied a last-gasp victory over Everton by the tightest and most contentious VAR call yet.
The two points that dubious decision cost Jurgen Klopp's side would have been hard enough to take without also losing Virgil van Dijk to an ACL injury which could possibly keep him out for the remainder of the season - a result of a reckless challenge from Jordan Pickford which somehow went unpunished by the on-field referee, the VAR referee and the post-match disciplinary panel.
Add to that injuries for Thiago Alcantara and Joel Matip and there is no doubt that it was a damaging day for the champions, despite Klopp being happy with their performance away to the league leaders.
Quite how Liverpool cope without Van Dijk is the question on everyone's lips and, given that they have already conceded 16 goals in eight games across all competitions, it is a puzzle which Ajax will be looking to put to the test here.
The Reds were crowned champions of Europe in 2018-19, when only an incredible Tottenham Hotspur comeback prevented Ajax from meeting them in the final, but they saw their defence ended at the round-of-16 stage last season as Atletico Madrid won home and away to progress just before lockdown.
Liverpool now face the prospect of losing three successive Champions League games for the first time since November 2014, and they head into the contest still without a win from their three October outings across all competitions.
The Merseysiders do boast an impressive record against Dutch opposition, though, remaining unbeaten in their last 13 such games - including six in a row away from home - since their last meeting with Ajax in December 1966.
By contrast, Ajax have only won one of their last six meetings with English sides, as well as just one win in their last seven home games in this competition against all opposition.
Indeed, while the four-time European champions will fancy their chances of progressing from a group which also contains Atalanta BC and FC Midtjylland, they have only managed to make it into the knockout rounds once from their last seven attempts - their unforgettable run to the semi-finals two years ago.
Erik ten Hag's side have lost a host of key players from that group since, but they have still started this season brightly with four wins from their opening five games.
The most recent of those was a 5-1 triumph over Heerenveen on Sunday, when Dusan Tadic scored a brace to help the Dutch giants maintain their 100% home record so far this term.
It is fair to say that none of their previous visitors have posed the same threat as Wednesday's will, although there may never be a better time to play this Liverpool side as they attempt to adapt to life without the man widely credited with turning them into such a European force again.
Ajax form (all competitions): WWWLW
Liverpool form (all competitions): WWWLLD
The news that Van Dijk could miss the remainder of the season with an ACL injury which requires surgery has unsurprisingly dominated the headlines in the wake of the Merseyside derby.
However, it is by no means Liverpool's only injury concern; Thiago - man of the match on his full debut at Goodison Park - was left with a knee injury which will be assessed ahead of kickoff after Richarlison's red-card challenge.
Fabinho may be forced into a makeshift centre-back role if Matip does not recover, but Liverpool's midfield ranks should be bolstered by Naby Keita, who is now back in training after being cleared to compete by a negative coronavirus test.
Ajax, meanwhile, are blessed with a clean bill of health for this match and could welcome the likes of Quincy Promes and Antony back into the side after they were named on the bench against Heerenveen.
Tadic has had a direct hand in 13 goals in 18 appearances in the Champions League - the most of any Ajax player since the start of the 2018-19 campaign.
Ajax possible starting lineup:
Onana; Mazraoui, Schuurs, Blind, Tagliafico; Klaassen, Kudus, Promes; Neres, Tadic, Antony
Liverpool possible starting lineup:
Adrian; Alexander-Arnold, Fabinho, Gomez, Robertson; Keita, Henderson, Wijnaldum; Salah, Firmino, Mane
We say: Ajax 1-2 Liverpool
Liverpool may not be in the best form in terms of results, but there was little wrong with their performance against Everton and if they produce a similar display in Amsterdam then they should win.
The big question mark surrounds how they will cope without Van Dijk, particularly against an Ajax attack with plenty of goals in them, but the impact of Liverpool's other stars certainly should not be ignored amid the loss of their centre-back.