The Reds go in search of their seventh European crown this year, while Milan are aiming to come up trumps on the continental stage for the eighth time.
The headlines from Liverpool's win over Leeds United at the weekend should have been centred around Mohamed Salah's 100th Premier League goal, but a horror injury to Harvey Elliott overshadowed what was otherwise a good day's work for the Reds at Elland Road.
Salah, Sadio Mane and Fabinho were all on target during a 3-0 win, but 18-year-old Elliott - who had begun to establish himself as a regular starter under Jurgen Klopp - was stretchered off with a dislocated ankle following a challenge from Pascal Struijk and is now set to go under the knife to rectify the issue.
Klopp has affirmed that Liverpool will "wait" for Elliott as he begins the long road to recovery, but the Reds cannot afford to dwell on the teenager's poor fortunes for a second as they seek to better their quarter-final finish in last season's Champions League, where Real Madrid sent them packing.
Having claimed three wins and three clean sheets from four Premier League matches so far this term - as well as extending their unbeaten streak to 13 matches in competitive action - Liverpool will seek a fast start to action in Group B, which also comprises Iberian giants Porto and Atletico Madrid.
Liverpool can also take encouragement from the fact that they have recorded three successive clean sheets in their last three Champions League home matches, and only one of their group-stage games at Anfield under Klopp has ended in defeat, although that came last season in a 2-0 loss to Atalanta BC.
Despite not being able to maintain a Scudetto charge in the 2020-21 top-flight campaign, AC Milan have once again started as they mean to go on with three wins out of three in Serie A so far, including a 2-0 success against Lazio on Sunday.
After Rafael Leao had opened the scoring on the stroke of half time, ageless striker Zlatan Ibrahimovic - now three weeks shy of his 40th birthday - came off the bench to wrap up the victory as the Rossoneri maintained their perfect start alongside Roma and Napoli.
The 2021-22 season marks AC Milan's return to the promised land of the Champions League after a painful eight-year absence from the top table - during which time they have only mustered two last-16 finishes in the Europa League - and five of their last six runs in the Champions League have also ended at that stage.
Wednesday's game will mark the first time that AC Milan have stepped foot onto the pitch for a Champions League tie since going down 4-1 to Atletico Madrid in the 2013-14 last-16 - not exactly a good omen with the La Liga champions also in their group - and they have claimed just one win from their last 13 ties against English opponents.
The miracle of Istanbul still lives fresh in the minds of the Liverpool faithful, but AC Milan gleaned revenge two years later with a 2-1 victory in the 2007 final, which represents the most recent meeting between two sides with 13 European titles between them.
Jordan Henderson was benched at the weekend but ought to come back in following Elliott's injury, while Alisson Becker and Fabinho were both cleared to play at Elland Road after the FIFA-imposed ban on Brazilian players was waived.
As for AC Milan, Olivier Giroud should be cleared to take part in this fixture after recovering from coronavirus, and the former Chelsea man will hope to reclaim his rightful place in attack over Ibrahimovic - who has been ruled out through injury - and Ante Rebic.
Tiemoue Bakayoko - who was allegedly the target of racist abuse at the weekend - lasted just 13 minutes as a substitute before going off injured against Lazio and is set for scans this week to determine the severity of the problem, while fellow midfielder Rade Krunic remains out.
Liverpool possible starting lineup:
Alisson; Alexander-Arnold, Van Dijk, Matip, Robertson; Henderson, Fabinho, Thiago; Salah, Jota, Mane
AC Milan possible starting lineup:
Maignan; Calabria, Tomori, Romagnoli, Hernandez; Kessie, Tonali; Florenzi, Diaz, Leao; Rebic
We say: Liverpool 1-1 AC Milan
With both of these European giants making fast starts to their domestic title challenges and seeking to carry that momentum over to continental competition, a tense and closely-fought affair should be in store on Merseyside.
There may be brief but well-documented history between Liverpool and AC Milan in the Champions League, but we are struggling to see either side gaining the upper hand and are backing a score draw in Wednesday's opener.